What hormone is produced by adipocytes to regulate satiety a feeling of fullness after eating

Leptin Signals the Repletion of Adipose Stores

Parabiosis (joining the circulatory systems of two animals to permit the exchange of hormones) between obese rats with medial basal hypothalamus lesions and nonlesioned rats led to starvation and weight loss in the latter, while parabiosis between two medial basal hypothalamus-lesioned rats did not alter energy balance in either animal.12–14 Thus medial basal hypothalamus-lesioned obese rats must produce a circulating factor that inhibits feeding in normal animals and acts via a medial basal hypothalamus satiety center.11 An important series of experiments by Douglas Coleman almost 50 years ago provided the first insights into a potential mediator of this effect. Coleman used mice homozygous forob, a recessive allele that causes hyperphagia, decreased energy expenditure, endocrine dysfunction, and obesity, and fordb, which lies at a different locus but produces a phenotype similar to that ofob. Parabiosis of lean (wild-type) mice withob/ob mice suppressed weight gain in theob/ob mice, whereas parabiosis of wild-type anddb/db mice caused profound hypophagia and weight loss in the wild-type mice.15–17 Based upon these results, Coleman predicted that theob locus produces a circulating satiety factor, while thedb locus encodes a component required for the response to the presumptiveob hormone.

Cloning of the causative gene mutations inob anddb strains confirmed the predictions of these parabiosis studies: The gene mutated inob encodes a hormone of the type 1 cytokine family (subsequently named leptin [from the Greekleptos, meaning “thin”]), whiledb affects the gene that encodes the leptin receptor (LepR), a member of the type 1 cytokine receptor family.18–20 Treatment with leptin decreases feeding, adipose mass, and body weight in leptin-deficientob/ob (Lepob/ob) mice and in lean normal mice, but fails to alterdb/db (Leprdb/db) mice.21–23

Adipose tissue produces leptin in approximate proportion to triglyceride stores, serving as a signal of the repletion of adipose energy stores to the central nervous system to control energy balance. Decreased leptin following caloric restriction initiates the neuroendocrine starvation response, increasing food-seeking and appetite and suppressing the expenditure of energy by neuroendocrine systems (resulting in infertility, decreased sympathetic nervous system tone, thyroid function, etc.).24,25 Exogenous leptin reverses the neuroendocrine manifestations of starvation as well as the neuroendocrine dysfunction ofLepob/ob mice. Leptin also reverses the hyperphagia, obesity, and neuroendocrine dysfunction of rare human patients with congenital leptin deficiency.26–28

Abstract

Leptin is the product of the obese (ob/ob) gene, homozygous mutations in which causes extreme obesity and associated phenotypes. Leptin is a circulating hormone produced by adipose cells, and the signaling form of the receptor, the product of the diabetes (db/db) gene, is expressed in hypothalamic neurons that are critical for the regulation of energy balance and glucose homeostasis. Unfortunately, after extensive basic and clinical research, it appears that neither leptin treatment or sensitization to leptin are generally effective to treat obesity. Instead the function of leptin is probably to signal nutritional deficit to produce appropriate neuroendocrine responses.

Role of Leptin in Host Resistance

Amebiasis is more common in malnourished children (a physiologic state of leptin deficiency). This suggests that the nutritional hormone leptin could play a protective role in amebiasis. In fact, a mutation in the leptin receptor was discovered that was associated with amebiasis susceptibility in children. The mutation is a nonconservative substitution (Q223R) in the extracellular cytokine receptor homology domain 1. The mutation accounted for the majority of susceptibility to amebiasis in children because it conferred a 3.9-fold greater risk of intestinal amebiasis and was present in almost half the children. The purely nutritional role of leptin did not explain protection because the Q223R mutation was not associated with children's nutritional status. Experiments in mice validated the human study, with leptin-deficient (ob/ob), leptin receptor–deficient (db/db), and 223R leptin receptor knock-in mice highly susceptible to intestinalE. histolytica infection. The site of leptin action was localized to the gut, because an intestinal epithelial cell–specific deletion of the leptin receptor rendered mice susceptible, whereas lack of the leptin receptor in the central nervous system or bone marrow–derived cells did not. Leptin receptor signal transducer and activator of transcription 3 (STAT3) and Src homology 2 domain–containing phosphatase 2 (SHP2) signaling were required for protection in vivo because susceptibility was conferred by mutation of tyrosine 985 or 1138, which mediate leptin signaling through the SHP2/extracellular signal–regulated kinase and STAT3 pathways, respectively. The importance of leptin signaling in prevention of amebic killing of the host could even be seen in single-cell studies, where transfection of human embryonic kidney cells with the leptin receptor rendered them resistant to amebic killing.130,131

Physiological Effects of Leptin

Leptin has been shown to produce a large number of physiological effects, especially in ob/ob mice, which, due to the absence of leptin, is highly sensitive to the effects of leptin. Current evidence indicates that most, if not all, of the effects of leptin are mediated through a small number of neurons in the hypothalamus. Such a possibility had been suspected because damage to the hypothalamus produces many symptoms, such as an increased food intake and body weight, as well as neuroendocrine impairments similar to those observed in ob/ob mice. The hypothesis was strongly supported by the observation that the form of the receptor that mediates the signaling of leptin is expressed mainly in hypothalamic neurons, and a direct infusion of leptin into the hypothalamus is sufficient to reproduce most or all of the metabolic effects of leptin. Although leptin receptors and effects of leptin have been reported in other tissues, the actions of leptin on neurons in the hypothalamus clearly account for the bulk of the metabolic and neuroendocrine effects of leptin. Key targets of leptin in the hypothalamus are neurons that produce proopiomelanocorticotropin (POMC), neuropeptide Y (NPY), melanin-concentrating hormone (MCH), and Agouti-related peptide (AgRP). Other satiety factors, including glucose, also appear to act on these neurons, suggesting that leptin is only one of the many factors that regulates the output of these neurons, and thus it is ultimately the state of these neurons, rather than leptin levels alone, that determine the metabolic status.

Although the primary sequence of leptin does not indicate its function, the crystal structure indicates that leptin is a cytokine-like molecule. This similarity is supported by the primary sequence of the leptin receptor, which indicates similarity to the class of cytokine receptors. Motivated by these observations, numerous studies have demonstrated that the leptin receptor acts through mechanisms common to other cytokine receptors, including activation of the Janus kinase/signal transducer and activator of transcription (STAT) system (especially STAT-3), and induction of the SOCS-3 gene, which acts in an anti-inflammatory negative-feedback fashion to restore the system to its initial state. It is hoped that a better understanding of the mechanisms by which leptin regulates hypothalamic function may lead to the development of drugs that enhance hypothalamic sensitivity to leptin, a pharmacological intervention that may be useful in treating obesity.

Mutations in the leptin receptor can, in some genetic backgrounds, lead to overt type-2 diabetes, a common complication of obesity. Leptin-deficient mice on the standard C57 genetic background are glucose-intolerant, though not overtly diabetic, again an expected consequence of the gross obesity that characterizes these mice. An expected consequence of leptin treatment in leptin-deficient mice (and humans) is an improvement in glucose tolerance, but the improvement is at least partially independent of reduction in body weight (as is the case with bariatric surgery). This improvement appears to be mediated almost entirely by hypothalamic POMC neurons, most likely through the autonomic nervous system acting at least in part on hepatic gluconeogenesis. Although this was an expected property of leptin, an even more remarkable property of leptin has recently received attention – it improves glucose control in models of type-1 diabetes, in which obesity plays no role. This observation highlights the role of hypothalamic neurons in regulating glucose homeostasis largely independent of insulin secretion. It remains to be determined whether leptin will be a useful adjuvant with insulin to treat type-1 diabetes in humans.

A rare disorder, called lipodystrophy, entails very low levels of adiposity, and can be caused by a number of conditions, including human immunodeficiency virus (HIV) infection. Lipodystrophy is generally accompanied by pathologically low levels of leptin, and may therefore also entail neuroendocrine impairments associated with leptin deficiency. Leptin treatment of individuals with lipodystrophy has been observed to improve some symptoms in case studies, including promoting puberty, but in randomized clinical trials results have been generally disappointing. Nevertheless, the neuroendocrine impairments associated with lipodystrophy are the most likely condition for which leptin treatment would be approved.

Leptin

Leptin is a 167–amino acid protein that is secreted primarily from adipocytes. Blood leptin levels reflect total body fat stores.128 Its primary action appears to be to reduce food intake. Leptin is a member of the cytokine family of signaling molecules. Five different forms of leptin receptors have been reported.129 A short form of the receptor appears to transport leptin from the blood across the blood-brain barrier, where it has access to the hypothalamus. A long form of the leptin receptor is located in hypothalamic nuclei, where leptin binds and activates the Janus kinase signal transduction and translation system (JAK STAT).130 Small amounts of leptin are produced by the chief cells of the stomach and by the placenta, and are present in breast milk.

Peripheral administration of leptin reduces food intake. However, this effect is reduced as animals become obese. Interestingly, when injected into the central nervous system, obese animals respond normally to leptin and reduce food intake, suggesting that leptin “resistance” in obesity occurs at the level of the leptin receptor that transports leptin across the blood-brain barrier.131 Leptin’s ability to reduce food intake occurs within the brain by decreasing NPY (a potent stimulant of food intake) and by increasing α–melanocyte-stimulating hormone (α−MSH), an inhibitor of food intake.132 Peripherally, leptin acts synergistically with CCK to reduce meal size.133 In obese rats lackingthe leptin receptor, the synergistic effects of leptin plus CCK to reduce meal size are lost, but could be restored with genetic reconstitution of the leptin receptor in the brain.134 One might expect loss of leptin-CCK synergy on meal size in those rare cases of human obesity caused by leptin receptor defects or even with leptin resistance.

Blood levels of leptin increase as obesity develops and leptin appears to reflect total fat content.135 At the cellular level, large adipocytes produce more leptin than small adipocytes. Because of its effects on food intake, it was initially thought that exogenous leptin could be used therapeutically to treat obesity. However, only a very modest effect on weight loss has been demonstrated in clinical trials. Leptin deficiency has been reported as a cause of obesity in a few families, but this condition is extremely rare.136,137 Mutation of the leptin receptor has been described as a cause of obesity in at least one family.138

Summary Points

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Leptin is a 167 amino acid hormone that circulates in the blood and can readily enter the brain.

Leptin and its receptors are expressed widely in the brain, suggesting that leptin is a pleiotropic hormone that regulates numerous CNS functions.

Leptin regulates food intake and body weight via its actions in the hypothalamus.

Leptin is a potential cognitive enhancer as it facilitates the cellular events underlying hippocampal-dependent learning and memory.

Leptin is implicated is various CNS-driven diseases, as dysfunctions in the leptin system have been linked to neurodegenerative disorders.

The leptin system is a potential therapeutic target in AD.

Leptin

Leptin is a hormone produced by adiposites; it signals energy sufficiency and satiety to the brain. It shows a regular diurnal rhythm, reaching maximal levels at night during sleep. Leptin’s primary site of action is located in the arcuate nucleus of the hypothalamus. Leptin levels drop during fasting, and it is a hormone known to be important for reproductive capacity. In women, menses ceases when leptin levels drop below normal levels and resume when leptin is supplemented as treatment. Leptin is also integrally involved in energy homeostasis and appetite regulation. Under conditions of total acute and prolonged partial sleep deprivation, leptin amplitude is reduced, with a lowered nocturnal peak.

Leptin and Puberty

Leptin, produced in adipose cells, can suppress appetite when it interacts with its receptor in the hypothalamus. Leptin plays a major role in pubertal development in mice and rats but has a modified role in human puberty. An extremely obese leptin-deficient girl aged 9 years had a bone age of 13 years which is compatible with the onset of normal puberty. She had no significant gonadotropin pulsatility and no secondary sexual development of puberty. After recombinant DNA-derived leptin was administrated to her, she began to demonstrate gonadotropin peaks, estrogen secretion increased, and secondary sexual development occurred. Individuals who are leptin resistant due to leptin receptor deficiency or abnormality will also have disorders of puberty. Leptin does not appear to trigger the onset of puberty in normal adolescents as changes in plasma leptin concentrations accompany pubertal changes rather than precede them. Leptin is necessary but not sufficient for pubertal development.

Leptin

Leptin is a 167-amino-acid protein hormone produced by adipose tissue that acts on specific receptors in the hypothalamus to decrease appetite and increase energy expenditure. Based on findings in rodents, which showed that leptin administration increased catecholamine turnover and sympathetic outflow to brown adipose tissue, kidneys, adrenal gland and hindlimb vasculature, it has been speculated that the sympathetic activation of human obesity may be mediated in part by increased plasma leptin levels. Obesity is known to be associated with circulating hyperleptinemia, reflecting a high fat mass and partial resistance to leptin. It has been postulated that leptin resistance in obesity can be selective, with preservation of sympathetic responsiveness despite resistance to satiety and the metabolic actions of leptin.

Our group has previously reported positive correlations between plasma leptin and renal norepinephrine spillover in men with widely differing adiposity, and between plasma leptin and whole-body norepinephrine spillover in obese metabolic syndrome subjects (Fig. 2C). Plasma leptin levels have also been associated with heart rate and MSNA in some but not all clinical studies and the associations are stronger in men than women. Leptin administration studies in humans have yielded heterogeneous findings. Machleidt et al. (2013) demonstrated that intravenous bolus administration of leptin increased MSNA in healthy nonobese men without alteration in baroreflex function, whereas in a separate investigation 6-day subcutaneous leptin infusion did not alter urinary catecholamine excretion. It is also relevant to note that subcutaneous obesity which is a state of hyperleptinemia is not linked to elevated MSNA. Thus, the evidence to support a role for leptin in contributing to sympathetic neural activation in human obesity remains equivocal at the present time.

Leptin

Leptin is a hormone that is released from white adipose cells. It has profound effects on food intake and body weight regulation, dramatically illustrated by the extreme obesity in both humans and rodents with genetic mutations to either the gene that encodes leptin or its receptor (LepRb). The effects of leptin on energy balance control are mediated largely by LepRb signaling in the hypothalamus [40], although leptin also signals in other brain regions to reduce food intake, including the ventral tegmental area [41] and the hippocampus [42]. Leptin’s action in the hippocampus promotes synaptic plasticity (long-term potentiation and long-term depression) [43], as well as neurogenesis [44], suggesting that leptin’s food intake suppressive effects in the hippocampus may be based on its ability to modulate memory function. Indeed, it was recently found that leptin signaling in the ventral subregion of the hippocampus suppressed the consolidation of memory for food location [42]. This latter finding is somewhat at odds with data showing that leptin increases neural plasticity (which is suggestive of memory promotion and not suppression). However, since higher leptin levels indicate energy sufficiency or surplus (more adipose tissue means more overall leptin), it may be that leptin signaling, at least in the ventral subregion of the hippocampus, modulates memory formation and retrieval in a manner that actively inhibits processing of food-related features of the environment in favor of nonfood features. Within this framework, rather than impairing memory formation and/or retrieval of food location, leptin may act in the hippocampus to promote the active inhibition of processing food-relevant cues to memory when these cues are less physiologically relevant (e.g., during satiety or when energy stores are sufficient).

The notion that leptin’s signaling capacity in the brain is compromised by obesity and dietary factors was based initially on the observation that while circulating leptin levels were directly related to the amount of adipose mass, obese humans and nonhuman animals continue to consume excess calories despite the excess amount of this anorexigenic signal. One mechanism to account for this purported “leptin resistance” is that the efficiency of leptin uptake at the BBB (i.e., rate of blood-to-brain transportation) is reduced for subjects with higher levels of adiposity [45]. A separate mechanism of leptin resistance was independently discovered, a phenomenon known as “cellular leptin resistance,” in which the ability of leptin to engage intracellular signaling pathways after binding to its receptor on neurons is impaired [46]. It should be noted, however, that the ability of Western diet consumption to promote either form of leptin resistance independent of increased adiposity and obesity has not yet been fully investigated.

The first of these two separate mechanisms of leptin resistance (reduced BBB transport from the periphery to the CNS) undoubtedly has implications with regard to leptin’s action on neurons in the hippocampus to modulate memory function. If less leptin is available in the CNS, the net effect is a downregulation of LeprB signaling in the hippocampus. Thus, this form of leptin resistance induced by Western diet intake and obesity may be an important underlying neurobiological mechanism to account for the detrimental impact of Western diet intake on cognition. With regard to cellular leptin resistance, thus far there is little evidence either for or against whether cellular leptin resistance occurs in the hippocampus as a result of Western diet intake.