Leptin (from
Greek
Greek may refer to:
Greece
Anything of, from, or related to Greece, a country in Southern Europe:
*Greeks, an ethnic group.
*Greek language, a branch of the Indo-European language family.
**Proto-Greek language, the assumed last common ancestor ...
λεπτός ''leptos'', "thin" or "light" or "small") is a
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
predominantly made by
adipose cells
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
and
enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its ...
s in the small intestine that helps to regulate
energy balance Energy balance may refer to:
* Earth's energy balance, the relationship between incoming solar radiation, outgoing radiation of all types, and global temperature change.
* Energy accounting, a system used within industry, where measuring and anal ...
by inhibiting
hunger
In politics, humanitarian aid, and the social sciences, hunger is defined as a condition in which a person does not have the physical or financial capability to eat sufficient food to meet basic nutritional needs for a sustained period. In the ...
, which in turn diminishes fat storage in
adipocyte
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
s.
Leptin is coded for by the ''LEP''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. Leptin acts on
cell receptor
In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a recepto ...
s in the
arcuate
''Arcuate'' (Latin for "curved") can refer to:
Anatomy
* Arcuate fasciculus
* Arcuate line (disambiguation)
* Arcuate artery (disambiguation), several arteries
* Arcuate nucleus
* Arcuate nucleus (medulla)
* Arcuate ligaments of the diaphragm
* A ...
and
ventromedial nuclei, as well as other parts of the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
and
dopaminergic neurons
Dopaminergic cell groups, DA cell groups, or dopaminergic nuclei are collections of neurons in the central nervous system that synthesize the neurotransmitter dopamine. In the 1960s, dopaminergic neurons or ''dopamine neurons'' were first ident ...
of the
ventral tegmental area
The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the ...
, consequently mediating
feeding
Eating (also known as consuming) is the ingestion of food, typically to provide a heterotrophic organism with energy and to allow for growth. Animals and other heterotrophs must eat in order to survive — carnivores eat other animals, herbi ...
.
Although regulation of fat stores is deemed to be the primary function of leptin, it also plays a role in other physiological processes, as evidenced by its many sites of synthesis other than fat cells, and the many cell types beyond hypothalamic cells that have
leptin receptor
Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor, a protein that in humans is encoded by the ''LEPR'' gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD295 ...
s. Many of these additional functions are yet to be fully defined.
In
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
, a decreased sensitivity to leptin occurs (similar to
insulin resistance
Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
in
type 2 diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
), resulting in an inability to detect
satiety
Satiety ( ) is a state or condition of fullness gratified beyond the point of satisfaction, the opposite of hunger. It is a state which induces meal termination.Hetherington, M.Sensory-specific satiety and its importance in meal termination ''Neuro ...
despite high energy stores and high levels of leptin. A synonym for ''LEP'' is ''OB'' (for obese).
Effects
![Fatmouse](https://upload.wikimedia.org/wikipedia/commons/0/0b/Fatmouse.jpg)
Predominantly, the "energy expenditure hormone" leptin is made by
adipose cells
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
, and is thus labeled ''fat cell-specific''. In the context of its
effects
Effect may refer to:
* A result or change of something
** List of effects
** Cause and effect, an idiom describing causality
Pharmacy and pharmacology
* Drug effect, a change resulting from the administration of a drug
** Therapeutic effect, a ...
, the short
describing words ''direct'', ''central'', and ''primary'' are not used interchangeably. In regard to the hormone leptin, central vs peripheral refers to the
hypothalamic
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus i ...
portion of the brain vs non-hypothalamic ''location of action'' of leptin; direct vs indirect refers to whether there is no intermediary, or there is an intermediary in the ''mode of action'' of leptin; and primary vs secondary is an arbitrary description of a particular ''function'' of leptin.
;Location of action: Leptin acts ''directly'' on
leptin receptor
Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor, a protein that in humans is encoded by the ''LEPR'' gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD295 ...
s in the
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
of different types of
cells
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
in the
human body
The human body is the structure of a Human, human being. It is composed of many different types of Cell (biology), cells that together create Tissue (biology), tissues and subsequently organ systems. They ensure homeostasis and the life, viabi ...
in particular, and in
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
s in general. The leptin receptor is found on a wide range of cell types. It is a ''single-transmembrane-domain''
type I cytokine receptor
Type I cytokine receptors are transmembrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands. These receptors are also known under the name '' hemopoietin receptors'', and share a ...
,
a special class of
cytokine receptor
Cytokine receptors are receptors that bind to cytokines.
In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly bec ...
s. Further, leptin interacts with other
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
s and energy regulators, ''indirectly'' mediating the effects of:
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
,
glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...
,
insulin-like growth factor
The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF "a ...
,
growth hormone
Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...
,
glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
s,
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s, and
metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s.
;Mode of action: The ''central'' location of action (''effect'') of the fat cell-specific hormone leptin is the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
, a part of the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
, which is a part of the central nervous system. Non-hypothalamic targets of leptin are referred to as ''peripheral'' targets. There is a different relative importance of central and peripheral leptin interactions under different
physiologic
Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...
states, and variations between species.
;Function: The ''primary'' function of the hormone leptin is the regulation of
adipose tissue
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...
mass through central hypothalamus mediated effects on
hunger
In politics, humanitarian aid, and the social sciences, hunger is defined as a condition in which a person does not have the physical or financial capability to eat sufficient food to meet basic nutritional needs for a sustained period. In the ...
,
food energy
Food energy is chemical energy that animals (including humans) derive from their food to sustain their metabolism, including their muscle, muscular activity.
Most animals derive most of their energy from aerobic respiration, namely combining the ...
use,
physical exercise
Exercise is a body activity that enhances or maintains physical fitness and overall health and wellness.
It is performed for various reasons, to aid growth and improve strength, develop muscles and the cardiovascular system, hone athletic ...
and
energy balance Energy balance may refer to:
* Earth's energy balance, the relationship between incoming solar radiation, outgoing radiation of all types, and global temperature change.
* Energy accounting, a system used within industry, where measuring and anal ...
. Outside the brain, in the periphery of the body, leptin's ''secondary'' functions are: modulation of energy expenditure, modulation between fetal and maternal metabolism, and that of a permissive factor in puberty, activator of immune cells, activator of beta islet cells, and growth factor.
Central nervous system
In vertebrates, the
nervous system
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
consists of two main parts, the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
(CNS) and the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
(PNS). The primary effect of leptins is in the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
, a part of the central nervous system. Leptin receptors are
expressed not only in the hypothalamus but also in other brain regions, particularly in the
hippocampus
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
. Thus some leptin receptors in the brain are classified as ''central'' (hypothalamic) and some as ''peripheral'' (non-hypothalamic).
As scientifically known so far, the general effects of leptin in the central nervous system are:
*Deficiency of leptin has been shown to alter brain proteins and neuronal functions of obese mice which can be restored by leptin injection.
*Leptin receptor signaling in the hippocampus enhances learning and memory.
Treatment with leptin has been shown to enhance learning and memory in animal models.
*In humans, low circulating plasma leptin has been associated with cognitive changes associated with anorexia,
depression, and Alzheimer's Disease.
*Studies in transgenic mouse models of Alzheimer's disease have shown that chronic administration of leptin can ameliorate brain pathology and improve cognitive performance,
by reducing b-amyloid and hyperphosphorylated Tau,
two hallmarks of Alzheimer's pathology.
Generally, leptin is thought to enter the brain at the
choroid plexus
The choroid plexus, or plica choroidea, is a plexus of cells that arises from the tela choroidea in each of the ventricles of the brain. Regions of the choroid plexus produce and secrete most of the cerebrospinal fluid (CSF) of the central nerv ...
, where the intense expression of a form of leptin receptor molecule could act as a transport mechanism.
Increased levels of
melatonin
Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle.
In vertebrates ...
causes a downregulation of leptin,
however, melatonin also appears to increase leptin levels in the presence of
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
, therefore causing a decrease in appetite during sleeping.
Partial sleep deprivation has also been associated with decreased leptin levels.
Mice with type 1 diabetes treated with leptin or leptin plus insulin, compared to insulin alone had better metabolic profiles: blood sugar did not fluctuate so much; cholesterol levels decreased; less body fat formed.
[*]
Hypothalamus
Leptin acts on
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
in the lateral
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
to inhibit hunger and the medial hypothalamus to stimulate satiety.
*In the lateral hypothalamus, leptin inhibits hunger
by
**counteracting the effects of
neuropeptide Y
Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the ma ...
, a potent hunger promoter secreted by cells in the gut and in the hypothalamus
**counteracting the effects of
anandamide
Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid rec ...
, another potent hunger promoter that binds to the same receptors as
THC
Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC'' ...
*In the medial hypothalamus, leptin stimulates satiety by
**promoting the synthesis of
α-MSH
α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone and neuropeptide of the melanocortin family, with a tridecapeptide structure and the amino acid sequence Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2. I ...
, a hunger suppressant
Thus, a lesion in the lateral hypothalamus causes anorexia (due to a lack of hunger signals) and a lesion in the medial hypothalamus causes excessive hunger (due to a lack of satiety signals).
This appetite inhibition is long-term, in contrast to the rapid inhibition of hunger by
cholecystokinin
Cholecystokinin (CCK or CCK-PZ; from Greek ''chole'', "bile"; ''cysto'', "sac"; ''kinin'', "move"; hence, ''move the bile-sac (gallbladder)'') is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and ...
(CCK) and the slower suppression of hunger between meals mediated by
PYY3-36
Peptide YY (PYY) also known as peptide tyrosine tyrosine is a peptide that in humans is encoded by the gene. Peptide YY is a short (36-amino acid) peptide released from cells in the ileum and colon in response to feeding. In the blood, gut, a ...
. The absence of leptin (or its receptor) leads to uncontrolled hunger and resulting obesity. Fasting or following a very-low-calorie diet lowers leptin levels.
Leptin levels change more when food intake decreases than when it increases. The dynamics of leptin due to an acute change in energy balance may be related to appetite and eventually, to food intake rather than fat stores.
* It controls food intake and energy expenditure by acting on receptors in the mediobasal
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
.
Leptin binds to
neuropeptide Y
Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the ma ...
(NPY) neurons in the
arcuate nucleus
The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several ...
in such a way as to decrease the activity of these neurons. Leptin signals to the hypothalamus which produces a feeling of satiety. Moreover, leptin signals may make it easier for people to resist the temptation of foods high in calories.
[*]
Leptin receptor activation inhibits neuropeptide Y and
agouti-related peptide
Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nu ...
(AgRP), and activates
α-melanocyte-stimulating hormone
α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone and neuropeptide of the melanocortin family, with a tridecapeptide structure and the amino acid sequence Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2. It ...
(α-MSH). The NPY neurons are a key element in the regulation of hunger; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic. Conversely, α-MSH is an important mediator of satiety, and differences in the gene for the α-MSH receptor are linked to obesity in humans.
Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf), which in turn are encoded by a single gene,
LEPR
Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor, a protein that in humans is encoded by the ''LEPR'' gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD295 ...
.
Ob-Rb is the only receptor isoform that can signal
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
ly via the
JAK-STAT
The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals out ...
and
MAPK
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
signal transduction pathways
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
,
and is present in
hypothalamic nuclei.
Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to effect changes in gene expression, one of the main effects being the down-regulation of the expression of
endocannabinoids
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
, responsible for increasing hunger.
In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them.
Circulatory system
The role of leptin/leptin receptors in modulation of
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
activity and the innate immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, of which obesity is a predisposing and exercise a mitigating factor.
Exogenous leptin can promote
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
by increasing
vascular endothelial growth factor
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
levels.
Hyperleptinemia produced by infusion or adenoviral gene transfer decreases blood pressure in rats.
Leptin microinjections into the
nucleus of the solitary tract
In the human brainstem, the solitary nucleus, also called nucleus of the solitary tract, nucleus solitarius, and nucleus tractus solitarii, (SN or NTS) is a series of purely sensory
nuclei (clusters of nerve cell bodies) forming a vertical column ...
(NTS) have been shown to elicit sympathoexcitatory responses, and potentiate the cardiovascular responses to activation of the chemoreflex.
Fetal lung
In
fetal lung, leptin is induced in the alveolar interstitial fibroblasts ("lipofibroblasts") by the action of
PTHrP secreted by formative alveolar epithelium (
endoderm
Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gast ...
) under moderate stretch. The leptin from the
mesenchyme
Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every o ...
, in turn, acts back on the epithelium at the leptin receptor carried in the alveolar type II pneumocytes and induces surfactant expression, which is one of the main functions of these type II pneumocytes.
Reproductive system
Ovulatory cycle
In mice, and to a lesser extent in humans, leptin is required for male and female
fertility
Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Fertili ...
. Ovulatory cycles in females are linked to energy balance (positive or negative depending on whether a female is losing or gaining weight) and energy flux (how much energy is consumed and expended) much more than energy status (fat levels). When energy balance is highly negative (meaning the woman is starving) or energy flux is very high (meaning the woman is exercising at extreme levels, but still consuming enough calories), the ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body fat percentage does energy status affect menstruation. Leptin levels outside an ideal range may have a negative effect on egg quality and outcome during ''in vitro'' fertilization.
Leptin is involved in reproduction by stimulating
gonadotropin-releasing hormone
Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...
from the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
.
Pregnancy
The placenta produces leptin. Leptin levels rise during pregnancy and fall after childbirth. Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin. Leptin plays a role in
hyperemesis gravidarum
Hyperemesis gravidarum (HG) is a pregnancy complication that is characterized by severe nausea, vomiting, weight loss, and possibly dehydration. Feeling faint may also occur. It is considered more severe than morning sickness. Symptoms often get ...
(severe
morning sickness
Morning sickness, also called nausea and vomiting of pregnancy (NVP), is a symptom of pregnancy that involves nausea or vomiting. Despite the name, nausea or vomiting can occur at any time during the day. Typically the symptoms occur between th ...
of pregnancy), in
polycystic ovary syndrome
Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...
and hypothalamic leptin is implicated in bone growth in mice.
Lactation
Immunoreactive leptin has been found in human breast milk; and leptin from mother's milk has been found in the blood of suckling infant animals.
Puberty
Leptin along with
kisspeptin
Kisspeptins (including kisspeptin-54 (KP-54), formerly known as metastin) are proteins encoded by the ''KISS1'' gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. ''Kiss1'' was originally identified as a human me ...
controls the onset of puberty.
High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche.
This may eventually lead to shorter
stature
Stature may refer to:
* Human stature, the distance from the bottom of the feet to the top of the head in a human body, standing erect
* Reputation, social opinion about an entity
* Respect
Respect, also called esteem, is a positive feeli ...
as
oestrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activ ...
secretion starts during menarche and causes early closure of
epiphyses
The epiphysis () is the rounded end of a long bone, at its joint with adjacent bone(s). Between the epiphysis and diaphysis (the long midsection of the long bone) lies the metaphysis, including the epiphyseal plate (growth plate). At the join ...
.
Bone
Leptin's role in regulating bone mass was identified in 2000.
Leptin can affect
bone metabolism
Bone remodeling (or bone metabolism) is a lifelong process where mature bone tissue is removed from the skeleton (a process called ''bone resorption'') and new bone tissue is formed (a process called ''ossification'' or ''new bone formation''). T ...
via direct signalling from the brain. Leptin decreases
cancellous bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, and ...
, but increases
cortical bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, and ...
. This "cortical-cancellous dichotomy" may represent a mechanism for enlarging bone size, and thus bone resistance, to cope with increased body weight.
Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue.
A number of brain-signalling molecules (
neuropeptides
Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
and
neurotransmitters
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neur ...
) have been found in bone, including
adrenaline
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
,
noradrenaline
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
,
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
,
calcitonin gene-related peptide
Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 ( intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produc ...
,
vasoactive intestinal peptide
Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a peptide of 28 amino acid residues that belongs to a glucagon/secretin superfamily, the ligan ...
and
neuropeptide Y
Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the ma ...
.
Leptin binds to its receptors in the hypothalamus, where it acts through the
sympathetic nervous system
The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of th ...
to regulate bone metabolism.
Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF-I pathway.
There is a potential for treatment of diseases of bone formation - such as impaired fracture healing - with leptin.
Immune system
Factors that acutely affect leptin levels are also factors that influence other markers of inflammation, e.g., testosterone, sleep, emotional stress, caloric restriction, and body fat levels. While it is well-established that leptin is involved in the regulation of the
inflammatory response,
it has been further theorized that leptin's role as an inflammatory marker is to respond specifically to adipose-derived inflammatory
cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
.
In terms of both structure and function, leptin resembles
IL-6 and is a member of the cytokine
superfamily
SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilies. Domains are functional, str ...
.
Circulating leptin seems to affect the
HPA axis HPA may refer to:
Organizations
* Harry Potter Alliance, a charity
* Halifax Port Authority, Canada
* Hamburg Port Authority, Germany
* Hawaii Preparatory Academy, a school in Hawaii, US
* Health Protection Agency, UK
* Heerespersonalamt, the Ger ...
, suggesting a role for leptin in stress response.
Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.
Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including
hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
,
metabolic syndrome
Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).
Metabolic syndrome ...
, and
cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
. While leptin is associated with body fat mass, the size of individual fat cells, and overeating, it is not affected by exercise (for comparison,
IL-6 is released in response to muscular contractions). Thus, it is speculated that leptin responds specifically to adipose-derived inflammation.
Leptin is a pro-angiogenic, pro-inflammatory and mitogenic factor, the actions of which are reinforced through crosstalk with IL-1 family cytokines in cancer.
High leptin levels have been also demonstrated in patients with COVID-19 pneumonia.
Taken as such, increases in leptin levels (in response to caloric intake) function as an acute pro-inflammatory response mechanism to prevent excessive cellular stress induced by overeating. When high caloric intake overtaxes the ability of fat cells to
grow larger or
increase in number in step with caloric intake, the ensuing stress response leads to inflammation at the cellular level and ectopic fat storage, i.e., the unhealthy storage of body fat within internal organs, arteries, and/or muscle. The insulin increase in response to the caloric load provokes a dose-dependent rise in leptin, an effect potentiated by high cortisol levels.
(This insulin-leptin relationship is notably similar to insulin's effect on the increase of IL-6 gene expression and secretion from
preadipocytes
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. ...
in a time- and dose-dependent manner.)
Furthermore, plasma leptin concentrations have been observed to gradually increase when
acipimox
Acipimox (trade name Olbetam in Europe) is a Niacin (substance), niacin derivative used as a lipid-lowering agent. It reduces triglyceride levels and increases High-density lipoprotein, HDL cholesterol.
It may have less marked adverse effects than ...
is administered to prevent
lipolysis
Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important ...
, concurrent hypocaloric dieting and weight loss notwithstanding.
Such findings appear to demonstrate high caloric loads in excess of storage rate capacities of fat cells lead to stress responses that induce an increase in leptin, which then operates as an adipose-derived inflammation stopgap signaling for the cessation of food intake so as to prevent adipose-derived inflammation from reaching elevated levels. This response may then protect against the harmful process of ectopic fat storage, which perhaps explains the connection between chronically elevated leptin levels and ectopic fat storage in obese individuals.
Leptin increases the production of leukocytes via actions on the hematopoietic niche, a pathway that is more active in sedentary mice and humans when compared to individuals which are physically active.
Location of gene and structure of hormone
The ''Ob(Lep)'' gene (Ob for obese, Lep for leptin) is located on
chromosome 7
Chromosome 7 is one of the 23 pairs of chromosomes in humans, who normally have two copies of this chromosome. Chromosome 7 spans about 159 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total DN ...
in humans.
Human leptin is a 16-kDa protein of 167 amino acids.
Mutations
A human mutant leptin was first described in 1997,
and subsequently six additional mutations were described. All of those affected were from Eastern countries; and all had variants of leptin not detected by the standard immunoreactive technique, so leptin levels were low or undetectable. The most recently described eighth mutation reported in January 2015, in a child with Turkish parents, is unique in that it ''is'' detected by the standard immunoreactive technique, where leptin levels are elevated; but the leptin does not turn on the leptin receptor, hence the patient has functional leptin deficiency.
These eight mutations all cause extreme obesity in infancy, with
hyperphagia
Polyphagia or hyperphagia is an abnormally strong, incessant sensation of hunger or desire to eat often leading to overeating. In contrast to an increase in appetite following exercise, polyphagia does not subside after eating and often leads to ...
.
Nonsense
A
nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...
in the leptin gene that results in a
stop codon
In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a codon (nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in me ...
and lack of leptin production was first observed in mice. In the mouse gene, arginine-105 is encoded by CGA and only requires one nucleotide change to create the stop codon TGA. The corresponding amino acid in humans is encoded by the sequence CGG and would require two nucleotides to be changed to produce a stop codon, which is much less likely to happen.
Frameshift
A recessive
frameshift mutation
A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet nature ...
resulting in a reduction of leptin has been observed in two
consanguineous
Consanguinity ("blood relation", from Latin '' consanguinitas'') is the characteristic of having a kinship with another person (being descended from a common ancestor).
Many jurisdictions have laws prohibiting people who are related by blood fro ...
children with juvenile obesity. A 2001 study of 13 people with a heterozygous frameshift mutation known as delta-G133 found that they had lower blood leptin levels than controls. There was an increased rate of obesity in these individuals, with 76% having a BMI of over 30 compared to 26% in the control group.
Polymorphisms
A Human Genome Equivalent (HuGE) review in 2004 looked at studies of the connection between genetic mutations affecting leptin regulation and obesity. They reviewed a common polymorphism in the leptin gene (A19G; frequency 0.46), three mutations in the
leptin receptor
Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor, a protein that in humans is encoded by the ''LEPR'' gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD295 ...
gene (Q223R, K109R and K656N) and two mutations in the ''
PPARG
Peroxisome proliferator- activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance
receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor functioning as a tran ...
'' gene (P12A and C161T). They found no association between any of the polymorphisms and obesity.
A 2006 study found a link between the common LEP-2548 G/A genotype and morbid obesity in
Taiwanese aborigines
Taiwanese may refer to:
* Taiwanese language, another name for Taiwanese Hokkien
* Something from or related to Taiwan ( Formosa)
* Taiwanese aborigines, the indigenous people of Taiwan
* Han Taiwanese, the Han people of Taiwan
* Taiwanese people, ...
,
but a 2014 meta-analysis did not,
however, this polymorphism has been associated with weight gain in patients taking antipsychotics.
The LEP-2548 G/A polymorphism has been linked with an increased risk of prostate cancer,
gestational diabetes,
and osteoporosis.
Other rare polymorphisms have been found but their association with obesity are not consistent.
Transversion
A single case of a homozygous
transversion mutation of the gene encoding for leptin was reported in January 2015.
It leads to functional leptin deficiency with high leptin levels in circulation. The transversion of (c.298G → T) changed
aspartic acid
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
to
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
at position 100 (p.D100Y). The mutant leptin could neither bind to nor activate the leptin receptor ''in vitro'', nor in leptin-deficient mice ''in vivo''. It was found in a two-year-old boy with extreme obesity with recurrent ear and pulmonary infections. Treatment with metreleptin led to "rapid change in eating behavior, a reduction in daily energy intake, and substantial weight loss."
Sites of synthesis
Leptin is produced primarily in the adipocytes of
white adipose tissue
White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes.
In humans, the healthy amount of white adipose ti ...
. It also is produced by
brown adipose tissue
Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals.
Classification of brown fat refers to two distinct cell populations with si ...
,
placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
(syncytiotrophoblasts),
ovaries
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
,
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
,
stomach
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
(the lower part of the
fundic glands
The gastric glands are glands in the lining of the stomach that play an essential role in the process of digestion. All of the glands have mucus-secreting foveolar cells. Mucus lines the entire stomach, and protects the stomach lining from the ef ...
),
mammary
A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in primat ...
epithelial cell
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
s,
bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
,
gastric chief cell
A gastric chief cell (or peptic cell, or gastric zymogenic cell) is a type of gastric gland cell that releases pepsinogen and gastric lipase. It is the cell responsible for secretion of chymosin in ruminant animals. The cell stains basophilic upo ...
s and
P/D1 cells.
Blood levels
Leptin circulates in blood in free form and bound to proteins.
Physiologic variation
Leptin levels vary exponentially, not linearly, with fat mass.
Leptin levels in blood are higher between midnight and early morning, perhaps suppressing appetite during the night.
The diurnal rhythm of blood leptin levels may be modified by meal-timing.
In specific conditions
In humans, many instances are seen where leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels:
* Leptin plays a critical role in the adaptive response to starvation.
* Leptin level is decreased after short-term
fasting
Fasting is the abstention from eating and sometimes drinking. From a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (see " Breakfast"), or to the metabolic state achieved after ...
(24–72 hours), even when changes in fat mass are not observed.
* Serum level of leptin is reduced by
sleep deprivation
Sleep deprivation, also known as sleep insufficiency or sleeplessness, is the condition of not having adequate duration and/or quality of sleep to support decent alertness, performance, and health. It can be either chronic or acute and may vary ...
.
* Leptin levels are paradoxically increased in
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
.
* Leptin level is increased by
emotional stress
In psychology, stress is a feeling of emotional strain and pressure. Stress is a type of psychological pain. Small amounts of stress may be beneficial, as it can improve athletic performance, motivation and reaction to the environment. Excess ...
.
* Leptin level is chronically reduced by
physical exercise
Exercise is a body activity that enhances or maintains physical fitness and overall health and wellness.
It is performed for various reasons, to aid growth and improve strength, develop muscles and the cardiovascular system, hone athletic ...
training
Training is teaching, or developing in oneself or others, any skills and knowledge or Physical fitness, fitness that relate to specific practicality, useful Competence (human resources), competencies. Training has specific goals of improving on ...
.
* Leptin level is decreased by increases in
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
levels and increased by increases in
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
levels.
* Leptin level is increased by
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
.
* Leptin release is increased by
dexamethasone
Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena cav ...
.
* In obese patients with
obstructive sleep apnea
Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder and is characterized by recurrent episodes of complete or partial obstruction of the upper airway leading to reduced or absent breathing during sleep. These episod ...
, leptin level is increased, but decreased after the administration of
continuous positive airway pressure
Continuous positive airway pressure (CPAP) is a form of positive airway pressure (PAP) ventilation in which a constant level of pressure greater than atmospheric pressure is continuously applied to the upper respiratory tract of a person. The ap ...
.
In non-obese individuals, however, restful sleep (i.e., 8–12 hours of unbroken sleep) can increase leptin to normal levels.
In mutations
All known leptin mutations except one are associated with low to undetectable immunoreactive leptin blood levels. The exception is a mutant leptin reported in January 2015 which is not functional, but is detected with standard immunoreactive methods. It was found in a massively obese -year-old boy who had high levels of circulating leptin which had no effect on leptin receptors, so he was functionally leptin-deficient.
Role in disease
Obesity
![Energy Balance](https://upload.wikimedia.org/wikipedia/commons/f/f7/Energy_Balance.png)
Although leptin reduces appetite as a circulating signal, obese individuals generally exhibit a higher circulating concentration of leptin than normal weight individuals due to their higher
percentage body fat.
These people show resistance to leptin, similar to
resistance of insulin in
type 2 diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
, with the elevated levels failing to control hunger and modulate their weight. A number of explanations have been proposed to explain this. An important contributor to leptin resistance is changes to leptin receptor signalling, particularly in the
arcuate nucleus
The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several ...
, however, deficiency of, or major changes to, the leptin receptor itself are not thought to be a major cause.
Triglyceride
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other vertebrates, as w ...
s crossing the
blood brain barrier
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the Cell (biology), cells, and transports Metabolic waste, metabolic waste products away from th ...
(BBB) can induce leptin and insulin resistance in the hypothalamus.
Triglycerides can also impair leptin transport across the BBB.
Studies on leptin
cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.
CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
(CSF) levels provide evidence for the reduction in leptin crossing the BBB and reaching obesity-relevant targets, such as the hypothalamus, in obese people.
In humans it has been observed that the ratio of leptin in the CSF compared to the blood is lower in obese people than in people of a normal weight.
The reason for this may be high levels of
triglycerides
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other vertebrates, as we ...
affecting the transport of leptin across the BBB or due to the leptin transporter becoming saturated.
Although deficits in the transfer of leptin from the plasma to the CSF is seen in obese people, they are still found to have 30% more leptin in their CSF than lean individuals.
These higher CSF levels fail to prevent their obesity. Since the amount and quality of leptin receptors in the hypothalamus appears to be normal in the majority of obese humans (as judged from leptin-mRNA studies),
it is likely that the leptin resistance in these individuals is due to a post leptin-receptor deficit, similar to the post-insulin receptor defect seen in type 2 diabetes.
When leptin binds with the leptin receptor, it activates a number of pathways. Leptin resistance may be caused by defects in one or more parts of this process, particularly the
JAK
Jak may refer to:
Places
* Ják, a village in Hungary
People
* Jak Alnwick (born 1993), English football goalkeeper
* Jak Jones (born 1993), Welsh professional snooker player
* Raymond Jackson ("JAK") (1927–1997), UK cartoonist
* Jak Airport ( ...
/
STAT
STAT, Stat. , or stat may refer to:
* Stat (system call), a Unix system call that returns file attributes of an inode
* ''Stat'' (TV series), an American sitcom that aired in 1991
* Stat (website), a health-oriented news website
* STAT protein, a ...
pathway. Mice with a mutation in the leptin receptor gene that prevents the activation of
STAT3
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family.
Function
STAT3 is a member of the STAT protein family. In respons ...
are obese and exhibit hyperphagia. The
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
pathway may also be involved in leptin resistance, as has been demonstrated in mice by artificial blocking of PI3K signalling. The PI3K pathway also is activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. The insulin-pI3K pathway can cause
POMC
Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the re ...
neurons to become insensitive to leptin through
hyperpolarization.
Leptin is known to interact with
amylin
Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone
Peptide hormones or protein hormones are hormones whose molecules are peptide, or proteins, respectively. The latter have longer amino acid chain lengths than the forme ...
, a hormone involved in gastric emptying and creating a feeling of fullness. When both leptin and amylin were given to obese, leptin-resistant rats, sustained weight loss was seen. Due to its apparent ability to reverse leptin resistance, amylin has been suggested as possible therapy for obesity.
It has been suggested that the main role of leptin is to act as a starvation signal when levels are low, to help maintain fat stores for survival during times of starvation, rather than a satiety signal to prevent overeating. Leptin levels signal when an animal has enough stored energy to spend it in pursuits besides acquiring food.
This would mean that leptin resistance in obese people is a normal part of mammalian physiology and possibly, could confer a survival advantage.
Leptin resistance (in combination with insulin resistance and weight gain) is seen in rats after they are given unlimited access to palatable, energy-dense foods.
This effect is reversed when the animals are put back on a low-energy diet.
This also may have an evolutionary advantage: allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food frequently may be scarce.
A
fad diet
A fad diet is a diet that becomes popular for a short time, similar to fads in fashion, without being a standard dietary recommendation, and often making unreasonable claims for fast weight loss or health improvements. There is no single defini ...
, the
Rosedale diet is based on ideas about how leptin might affect weight. It is based on unsound science and marketed with unevidenced claims of health benefits.
Role in osteoarthritis with obesity
Obesity and osteoarthritis
Osteoarthritis and obesity are closely linked. Obesity is one of the most important preventable factors for the development of osteoarthritis.
Originally, the relationship between osteoarthritis and obesity was considered to be exclusively biomechanically based, according to which the excess weight caused the joint to become worn down more quickly. However, today we recognise that there is also a metabolic component which explains why obesity is a risk factor for osteoarthritis, not only for weight-bearing joints (for example, the knees), but also for joints that do not bear weight (for example, the hands).
Consequently, it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se.
This metabolic component related with the release of systemic factors, of a pro-inflammatory nature, by the adipose tissues, which frequently are critically associated with the development of osteoarthritis.
Thus, the deregulated production of adipokines and inflammatory mediators, hyperlipidaemia, and the increase of systemic oxidative stress are conditions frequently associated with obesity which can favour joint degeneration. Furthermore, many regulation factors have been implicated in the development, maintenance and function, both of adipose tissues, as well as of the cartilage and other joint tissues. Alterations in these factors can be the additional link between obesity and osteoarthritis.
Leptin and osteoarthritis
Adipocytes interact with other cells through producing and secreting a variety of signalling molecules, including the cell signalling proteins known as adipokines. Certain adipokines can be considered as hormones, as they regulate the functions of organs at a distance, and several of them have been specifically involved in the physiopathology of joint diseases. In particular, there is one, leptin, which has been the focus of attention for research in recent years.
The circulating leptin levels are positively correlated with the Body Mass Index (BMI), more specifically with fatty mass, and obese individuals have higher leptin levels in their blood circulation, compared with non-obese individuals.
In obese individuals, the increased circulating leptin levels induce unwanted responses, that is, reduced food intake or losing body weight does not occur as there is a resistance to leptin (ref 9). In addition to the function of regulating energy homeostasis, leptin carries out a role in other physiological functions such as neuroendocrine communication, reproduction, angiogenesis and bone formation. More recently, leptin has been recognised as a cytokine factor as well as with pleiotropic actions also in the immune response and inflammation.
For example, leptin can be found in the synovial fluid in correlation with the body mass index, and the leptin receptors are expressed in the cartilage, where leptin mediates and modulates many inflammatory responses that can damage cartilage and other joint tissues. Leptin has thus emerged as a candidate to link obesity and osteoarthritis and serves as an apparent objective as a nutritional treatment for osteoarthritis.
As in the plasma, the leptin levels in the synovial fluid are positively correlated with BMI.
The leptin of the synovial fluid is synthesised at least partially in the joint and may originate in part in the circulation. Leptin has been shown to be produced by chondrocytes, as well as by other tissues in the joints, including the synovial tissue, osteophytes, the meniscus and bone.
An infrapatellar fat pad located extrasynovially within the knee joint is also adjacent to the synovial membrane and cartilage, and has recently been highly appreciated as an important source of leptin, as well as other adipokines and mediators which contribute to the pathogenesis of osteoarthritis
The risk of suffering osteoarthritis can be decreased with weight loss. This reduction of risk is related in part with the decrease of the load on the joint, but also in the decrease of fatty mass, the central adipose tissue and the low-level inflammation associated with obesity and systemic factors.
This growing evidence points to leptin as a cartilage degradation factor in the pathogenesis of osteoarthritis, and as a potential biomarker in the progression of the disease, which suggests that leptin, as well as regulation and signalling mechanisms, can be a new and promising target in the treatment of osteoarthritis, especially in obese patients.
Obese individuals are predisposed to developing osteoarthritis, not only due to the excess mechanical load, but also due to the excess expression of soluble factors, that is, leptin and pro-inflammatory cytokines, which contribute to joint inflammation and cartilage destruction. As such, obese individuals are in an altered state, due to a metabolic insufficiency, which requires specific nutritional treatment capable of normalising the leptin production and reducing the systematic low-level inflammation, in order to reduce the harmful impact of these systematic mediators on the joint health.
There are nutritional supplements and pharmacological agents capable of directing these factors and improving both conditions.
Therapeutic use
Leptin
Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized
lipodystrophy
Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissue. ...
.
Analog metreleptin
An analog of human leptin
metreleptin
Metreleptin, sold under the brand name Myalept among others, is a synthetic analog of the hormone leptin used to treat various forms of dyslipidemia. It has been approved in Japan for metabolic disorders including lipodystrophy and in the United ...
(trade names Myalept, Myalepta) was first approved in Japan in 2013, and in the United States in February 2014 and in Europe in 2018. In the US it is indicated as a treatment for complications of leptin deficiency, and for the diabetes and
hypertriglyceridemia
Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and h ...
associated with congenital or acquired generalized
lipodystrophy
Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissue. ...
.
In Europe based on
EMA, metreleptin should be used in addition to diet to treat lipodystrophy, where patients have loss of fatty tissue under the skin and build-up of fat elsewhere in the body such as in the liver and muscles. The medicine is used in adults and children above the age of 2 years with
generalised lipodystrophy (
Berardinelli-Seip syndrome
Congenital generalized lipodystrophy (also known as Berardinelli–Seip lipodystrophy) is an extremely rare autosomal recessive condition, characterized by an extreme scarcity of fat in the subcutaneous tissues. It is a type of lipodystophy disord ...
and
Lawrence syndrome); and in adults and children above the age of 12 years with
partial lipodystrophy
Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissue. ...
(including
Barraquer-Simons syndrome), when standard treatments have failed.
The National Health Service in England will commission metreleptin treatment for all with congenital leptin deficiency regardless of age beginning on April 1, 2019.
History
The leptine was discovered by Jeffrey Friedman in 1994 after several decades of research conducted by others institutions since 1950 on obese mouse models
Identification of the encoding gene
In 1949, a non-obese mouse colony being studied at the
Jackson Laboratory
The Jackson Laboratory (often abbreviated as JAX) is an independent, non-profit biomedical research institution which was founded by a eugenicist. It employs more than 3,000 employees in Bar Harbor, Maine; Sacramento, California; Farmington, Con ...
produced a strain of obese offspring, suggesting that a mutation had occurred in a hormone regulating hunger and energy expenditure. Mice homozygous for the so-called ob mutation (ob/ob) ate voraciously and were massively obese. In the 1960s, a second mutation causing obesity and a similar phenotype was identified by
Douglas Coleman Douglas L. Coleman (6 October 1931 – 16 April 2014) was a scientist and professor at The Jackson Laboratory, in Bar Harbor, Maine. His work predicted that the ob gene encoded the hormone leptin, later co-discovered in 1994 by Jeffrey Friedman, Ru ...
, also at the Jackson Laboratory, and was named diabetes (db), as both ob/ob and db/db were obese.
In 1990
Rudolph Leibel
Rudolph Leibel (born 1942) is the Christopher J. Murphy Professor of Diabetes Research, Professor of Pediatrics and Medicine at Columbia University Medical Center, and Director of the Division of Molecular Genetics in the Department of Pediatrics ...
and
Jeffrey M. Friedman reported mapping of the ''db'' gene.
Consistent with Coleman's and Leibel's hypothesis, several subsequent studies from Leibel's and Friedman's labs and other groups confirmed that the ob gene encoded a novel hormone that circulated in blood and that could suppress food intake and body weight in ob and wild type mice, but not in db mice.
In 1994, Friedman's laboratory reported the identification of the gene.
In 1995,
Jose F. Caro
José F. Caro, M.D. (born Granada, Spain, 1948) is an American physician, scientist, and educator most notable for his research in obesity and diabetes. The Institute for Scientific Information listed him the third most cited investigator in the wo ...
's laboratory provided evidence that the mutations in the mouse ob gene did not occur in humans. Furthermore, since ob gene expression was increased, not decreased, in human obesity, it suggested resistance to leptin to be a possibility.
At the suggestion of
Roger Guillemin
Roger Charles Louis Guillemin (born January 11, 1924) is a French-American neuroscientist. He received the National Medal of Science in 1976, and the Nobel prize for medicine in 1977 for his work on neurohormones, sharing the prize that year w ...
, Friedman named this new hormone "leptin" from the Greek ''lepto'' meaning thin.
Leptin was the first fat cell-derived hormone (
adipokine
The adipokines, or adipocytokines (Greek ', fat; ', cell; and ', movement) are cytokines (cell signaling proteins) secreted by adipose tissue. Some contribute to an obesity-related low-grade state of inflammation or to the development of metabolic ...
) to be discovered.
Subsequent studies in 1995 confirmed that the db gene encodes the
leptin receptor
Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor, a protein that in humans is encoded by the ''LEPR'' gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD295 ...
, and that it is expressed in the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
, a region of the brain known to regulate the sensation of hunger and body weight.
Recognition of scientific advances
Coleman and Friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin, including the
Gairdner Foundation International Award
The Canada Gairdner International Award is given annually by the Gairdner Foundation at a special dinner to five individuals for outstanding discoveries or contributions to medical science. Receipt of the Gairdner is traditionally considered a p ...
(2005), the
Shaw Prize
The Shaw Prize is an annual award presented by the Shaw Prize Foundation. Established in 2002 in Hong Kong, it honours "individuals who are currently active in their respective fields and who have recently achieved distinguished and signifi ...
(2009), the
Lasker Award
The Lasker Awards have been awarded annually since 1945 to living persons who have made major contributions to medical science or who have performed public service on behalf of medicine. They are administered by the Lasker Foundation, which was f ...
,
the
BBVA Foundation Frontiers of Knowledge Award
The BBVA Foundation Frontiers of Knowledge Awards () are an international award programme recognizing significant contributions in the areas of scientific research and cultural creation. The categories that make up the Frontiers of Knowledge Awards ...
and the
King Faisal International Prize
The King Faisal Prize ( ar, جائزة الملك فيصل, formerly King Faisal International Prize), is an annual award sponsored by King Faisal Foundation presented to "dedicated men and women whose contributions make a positive difference". T ...
,
Leibel has not received the same level of recognition from the discovery because he was omitted as a co-author of a scientific paper published by Friedman that reported the discovery of the gene. The various theories surrounding Friedman's omission of Leibel and others as co-authors of this paper have been presented in a number of publications, including
Ellen Ruppel Shell
Ellen Ruppel Shell (born 1952Pearson Education (2008). Shell, Ellen Ruppel. Retrieved on 2009-08-10 from http://wps.prenhall.com/hss_kirszner_blairreader_5/24/6255/1601495.cw/index.html .) is a correspondent for ''The Atlantic Monthly'', and profe ...
’s 2002 book ''
The Hungry Gene
''The Hungry Gene'' is a 2002 book by Ellen Ruppel Shell in which she tackles the issue of obesity. It is a non-fiction journalistic book. The author devotes multiple chapters of her book to the events that led to the co-discovery of the Leptin ge ...
''.
[ ]
The discovery of leptin also is documented in a series of books including ''Fat: Fighting the Obesity Epidemic'' by Robert Pool, ''
The Hungry Gene
''The Hungry Gene'' is a 2002 book by Ellen Ruppel Shell in which she tackles the issue of obesity. It is a non-fiction journalistic book. The author devotes multiple chapters of her book to the events that led to the co-discovery of the Leptin ge ...
'' by Ellen Ruppel Shell, and ''Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting'' by
Gina Kolata
Gina Bari Kolata (born February 25, 1948) is an American science journalist, writing for ''The New York Times''.
Life and career
Kolata was born Gina Bari in Baltimore, Maryland. Her mother, mathematician Ruth Aaronson Bari (1917–2005), was o ...
.
''Fat: Fighting the Obesity Epidemic'' and ''Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting'' review the work in the Friedman laboratory that led to the cloning of the ob gene, while The ''Hungry Gene'' draws attention to the contributions of Leibel.
See also
*
Ghrelin
Ghrelin (; or lenomorelin, INN) is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highe ...
*
NAPEs
''N''-Acylphosphatidylethanolamines (NAPEs) are hormones released by the small intestine into the bloodstream when it processes fat. NAPEs travel to the hypothalamus in the brain and suppress appetite. This mechanism could be relevant for treating ...
*
Teleost leptins
References
External links
Leptin: Your brain, appetite and obesity by the British Society of Neuroendocrinology– last updated 1998
Leptin at 3Dchem.com description and structure diagrams
*
{{Commons category, Leptin (obesity protein), Leptin
Leptin receptor agonists
Peptide hormones
Mutated genes
Obesity