it has structural homology with the cytokines of the long - chain helical family that includes interleukin ( il)-6 , il-11 , il-12 , and oncostatin m , and therefore is part of the adipokines family .
leptin regulates food intake and energy expenditure , and has also multiple actions in the endocrine and immune systems , including fertility , bone formation , tissue remodeling , and inflammation . within the endocrine system
it also plays key roles in the regulation of glucose homeostasis and insulin sensitivity , independent of actions on food intake , energy expenditure or body weight . in this review ,
we present evidence for leptin 's actions on the glucose - insulin homeostasis , and highlight its current and future applications for treating disorders of the glucose - insulin homeostasis .
its levels are correlated with fat mass , and the increase in human or rodent fat masses due to genetic manipulation or environmental induction causes an increase in leptin levels .
several metabolic and hormonal factors influence the synthesis and secretion of leptin in the body , such as cytokines , cortisol , catecholamines , fatty acids , glucose , and insulin .
there are at least four different isoforms of the leptin receptor in humans : o0 b - ra , ob - rb , and ob - rc ( membrane - anchored ) , and ob - re ( soluble ) ; these are all products of alternatively spliced forms of the ob - r gene .
the membrane - anchored isoforms have identical extracellular , ligand - binding and transmembrane domains , with different lengths of the intracellular domain .
the isoform ob - rb contains a long cytoplasmic region containing several motifs required for signal transduction and capable of activating the jak - stat signal transduction pathway .
ob - ra is regarded as the leptin transporter across the blood - brain barrier and leptin degrader .
the secreted soluble isoform ( ob - re ) lacks both the intracellular and transmembrane domains , and serves as plasmatic leptin - binding protein .
these isoforms are involved in mediating leptin 's actions in the brain and in peripheral organs .
two other isoforms have not been identified in humans : o0 b - rd has been identified in mice and ob - rf , in rats only .
the transduction of leptin 's signals is mediated by known pathways , namely janus kinase - signal transducer and activator of transcription ( jak - stat ) , extracellular signal - regulated kinase ( erk)-1/2 , phosphatidylinositol-3-kinase ( pi3k ) , and amp - activated protein kinase ( ampk ) . the ampk pathway is particularly involved in preventing insulin resistance , in part by inhibiting pathways that antagonize insulin signaling .
intracellular mechanisms are activated to down - regulate leptin 's actions , mediated mainly by the suppressor of cytokine signaling 3 ( socs3 ) . and protein tyrosine phosphatase 1b ( ptp1b ) , which are implicated in the mechanisms of leptin resistance . the most important function of leptin is the regulation of energy expenditure and food intake , due to its actions on the arcuate nucleus of the hypothalamus .
in this area , leptin binds to its receptors , which are expressed in two different neuronal populations : the ones that express agouti - related peptide ( agrp ) and neuropeptide y ( npy ) , and those that express the peptide cocaine and amphetamine - related transcript ( cart ) and the large precursor peptide pro - opiomelanocortin ( pomc ) .
leptin exerts anorexigenic effects by inhibiting the agrp / npy neurons and by stimulating the pomc / cart neurons .
several other effects have been attributed to leptin , mostly from studies with leptin - deficient animal and human models .
among mice that are leptin - deficient ( ob / ob ) or leptin - resistant ( db / db , due to mutations in the leptin receptor gene causing lack of leptin signaling ) , hyperphagia is a constant and obesity , a hallmark .
this adipocyte - derived hormone regulates nutritional status by controlling both energy intake and energy expenditure . in the absence of leptin
, rodents and humans alike suffer from massive obesity with a voracious appetite and a blunted metabolic rate.[1922 ] subjects with very low plasma leptin concentrations have large body weight gains over relatively short periods of time .
leptin - deficient mice ( ob / ob ) carry a spontaneous missense mutation in their leptin gene .
they also have dyslipidemia , hypercortisolism , low levels of growth hormone , central hypothyroidism , hypogonadotropic hypogonadism , and cellular immune deficiency.[192224 ] in the leptin deficient ob / ob mouse model , obese phenotype is prevented and reversed by the administration of exogenous leptin . in humans , leptin deficiency can be observed in several conditions , such as lipodystrophy syndromes , anorexia nervosa , hypothalamic amenorrhea , and congenital leptin deficiency . for over 13 years
, our group has been evaluating phenotypic findings and the effects of leptin replacement in four unique leptin - deficient adults from a consanguineous extended turkish family .
these individuals have a mendelian recessive mutation in the leptin gene , consisting of a ct substitution in codon 105 of this gene , resulting in an argtrp replacement in the mature protein .
physiological doses of recombinant methionyl human leptin ( r - methuleptin , metreleptin , amylin pharmaceuticals , usa , 0.02 - 0.04 mg / kg / day ) were initiated on the leptin - deficient individuals being assessed by our group at ages 5 ( boy ) , 27 ( male ) , 30 and 40 ( females ) .
leptin replacement was lifesaving , as eight members of this family with severe early - onset obesity , whom we presume to have been leptin - deficient , died during childhood due to infections . by evaluating leptin - deficient patients while on leptin replacement , and after brief periods of leptin withdrawal
, we have observed that leptin regulates the circadian rhythms of cortisol , thyroid stimulating hormone , luteinizing hormone and follicle - stimulating hormone . in the brain ,
leptin controls energy balance and body weight , and plays a role in neurogenesis and brain function .
leptin enhances immune response , and regulates inflammation , coagulation , fibrinolysis , and platelet aggregation . within the adipoinsular axis
, we have observed that leptin decreases insulin and glucose levels . in its absence ,
insulin sensitivity is markedly increased due to rapid weight gain ( discussed with more detail ahead ) .
the adipose tissue plays an important role in total energy homeostasis . glucose and lipid metabolism
abnormal accumulation of triglycerides in non - adipose tissues , caused by the upregulation of lipogenesis , leads to a deleterious state known as lipotoxicity .
lipotoxicity is characterized as the accumulation of triglycerides in the surrounding hepatocytes and is thought to be a major contributor to islet cell transplantation failure in diabetics.[3538 ] lipotoxicity also contributes to the increase in insulin resistance .
given that leptin is thought to oppose insulin action by decreasing hepatocyte lipogenesis , leptin administration may result in decreased lipotoxicity , being useful for the treatment of lipodystrophy syndromes .
however , when used for treating obesity - associated non - alcoholic fatty liver disease , leptin might instead promote insulin resistance , fibrosis , and hepatocellular carcinoma .
a majority of the studies suggest that leptin decreases insulin synthesis and secretion by pancreatic beta cells , and increases insulin hepatic extraction.[4144 ] as a result , insulin delivery is reduced by leptin .
this so - called adipoinsular axis is part of a leptin - mediated inhibitory feedback on insulin secretion in order to decrease adipogenesis .
leptin also decreases hepatic glucose production , increases insulin sensitivity , and decreases glucagon levels .
insulin , in turn , also plays a role in stimulating leptin production and secretion in the adipose tissue .
effects of leptin on the glucose - insulin metabolism hypothalamic insulin and leptin signaling play a crucial role in the regulation of glucose homeostasis and in the development of insulin resistance .
centrally , insulin modulates hepatic glucose production , skeletal muscle glycogen synthesis , brown adipose tissue thermogenesis , and white adipose tissue lipolysis .
central leptin , in turn , regulates hepatic gluconeogenesis and insulin sensitivity , skeletal - muscle lipid oxidation and glucose uptake / utilization , brown adipose tissue glucose uptake and white adipose tissue lipolysis , and insulin secretion .
these effects seem to be mediated by the autonomic regulation of skeletal muscle , liver , pancreas and adipose tissues . in the hypothalamus ,
the leptin signaling pi3k pathway plays an important role in decreasing peripheral insulin resistance , as central leptin improved tolerance to glucose , increased pgc1 alpha expression , and regulated akt , ampk , acc and jak2 phosphorylation in the soleus muscle of rats fed with regular chow . in untreated diabetic mice ,
hypoleptinemia caused by decreased fat mass leads to severe insulin resistance , which is reversed by leptin replacement , giving support to the usefulness of leptin in the treatment of diabetes .
it has been shown that direct action of insulin and leptin on the pomc neurons is required to maintain normal glucose homeostasis . in ob - r deficient mice , restoring leptin receptor expression only at pomc neurons normalizes blood glucose and ameliorates hepatic insulin resistance , hyperglucagonemia , and dyslipidemia , independent of changes in body weight .
it has been calculated that 42% of leptin 's hypoglycemic action is independent of weight reduction .
the effects of leptin can be explained by its actions in increasing hypothalamic insulin sensitivity .
however , it has also been demonstrated that leptin ameliorates hyperglycemia by suppressing hepatic glucose production and by increasing tissue glucose uptake , independent of insulin .
another potential mechanism by which leptin ameliorates glucose levels is the increase in igf binding protein 2 ( igfbp2 ) level , which reduces blood glucose in wild - type and diabetic mice , and potently suppresses hepatic glucose production , as well as genes involved in hepatic gluconeogenesis and fatty acid synthesis .
osteocalcin is a marker of bone formation that is synthesized and secreted by the osteoblasts .
osteocalcin increases insulin expression and insulin sensitivity in animals , and mice that lack osteocalcin are glucose intolerant .
it has been shown that the inhibition of insulin secretion exerted by leptin is partly mediated by leptin 's effect on inhibiting the metabolic activity of osteocalcin : leptin stimulates the sympathetic tone , which in turn stimulates the expression of esp , a gene that inhibits osteocalcin . in humans , osteocalcin has been associated negatively with insulin resistance , and leptin has been correlated negatively with osteocalcin levels both in cross - sectional and longitudinal analyses .
therefore , obesity may lead to insulin resistance through a leptin - mediated suppression of osteocalcin .
however , the stimulatory role of osteocalcin on pancreatic insulin secretion has been questioned by studies showing that elevated osteocalcin is associated with suppressed blood insulin .
wild - type , ob / ob and non - obese , diabetic insulinopenic akita mice submitted to a single intracerebroventricular ( icv ) injection of recombinant adeno - associated virus vector encoding leptin gene ( raav - lep ) showed increased blood osteocalcin levels , and decreased insulin levels .
this suggests that the inhibitory effect of leptin on insulin secretion is limited by high circulating levels of osteocalcin , or that the osteocalcin stimulatory and insulin inhibitory effects are mediated by independent central leptin feedback mechanisms .
leptin replacement reverses insulin resistance and diabetes in mice homozygous for mutations of the ob gene , in ap2-nsrebp-1 c mice with moderate fat deficiency , and in severely lipoatrophic a - zip / f-1 mice . in non - obese diabetic ( nod ) mice , leptin therapy alone or combined with low - dose insulin reverses the catabolic state through suppression of hyperglucagonemia , mimics the anabolic actions of insulin , and normalizes hemoglobin a1c .
in contrast with insulin , leptin lowers lipogenic and cholesterologenic transcription factors and reduces plasma and tissue lipids .
therefore , leptin and insulin may become a potential combination therapy for type 1 diabetes , but there are concerns regarding hypoglycemia .
intracerebroventricular infusion of leptin improved hyperglycemia , hyperglucagonemia , hyperketonemia , and polyuria caused by insulin deficiency in nod mice , independent of hepatic signaling .
therefore , leptin may improve insulin resistance not only by decreasing body weight and fat mass , but also by activating insulin - sensitive tissues such as the adipose tissue and liver .
the activation of the jak - stat , pi3k , and ampk pathways , which overlap with those of insulin , contributes to the leptin - mediated decrease in insulin resistance .
however , other in vitro and in vivo studies are contradictory , suggesting that leptin may in fact increase insulin resistance.[416769 ] gene therapy through icv injection of recombinant adeno - associated virus vector encoding the leptin gene ( raav - lep ) has been shown to normalize glucose levels in animal models of diabetes type 1 and 2 , by stimulating glucose disposal , by increasing energy expenditure from peripheral organs such as brown adipose tissue , by improving insulin sensitivity , and by suppressing pancreatic insulin secretion in diabetes type 2 models .
besides being a potentially safe and effective antidiabetic therapy , these results clearly demonstrate that leptin regulates the glucose - insulin homeostasis in the hypothalamus , independent of its peripheral actions . in humans ,
leptin is positively correlated with insulin resistance , independently of body weight or adiposity , both in normoglycaemic and in diabetic patients .
in obese patients with type 2 diabetes , metreleptin administration did not alter body weight or circulating inflammatory markers but reduced hba1c marginally , from 8.010.93% to 7.961.12% ( p = 0.03 ) .
in addition , treatment did not have weight loss - independent , clinically important effects on insulin sensitivity in those patients .
human studies evaluated the insulin - sensitizing effects of leptin replacement in patients with lipodystrophy.[7780 ] humans with lipoatrophic disorders ( exhibiting very low levels of leptin , increased insulin resistance and hyperinsulinemia ) experienced a decrease in insulin resistance after treatment with r - methuleptin.[7780 ] hemoglobin a1c reduced by 1.5% in a group of 48 patients with lipodystrophy treated with recombinant methionyl human leptin .
those results may be biased because those patients lack adipose tissue , and have a presumably defective adipoinsular axis .
leptin - deficient humans therefore , provide a unique opportunity to evaluate the effects of leptin on insulin resistance.[8284 ] in a cohort of three leptin - deficient adults , we have previously observed that before treatment with metreleptin , all patients had high insulin and lipid levels .
leptin replacement normalized serum lipids , insulin and glucose levels , and led to the resolution of type 2 diabetes .
meal tolerance tests performed before and after leptin replacement showed increased insulin sensitivity ( by 5.7-fold ) and decreased insulin secretion ( by 2-fold ) , while insulin hepatic extraction returned to rates close to normal .
paradoxically , after leptin withdrawal , insulin sensitivity increased further , as measured by euglycemic hyperinsulinemic clamps [ figure 1 ] . this might be attributed to the rapid gain in glucose - absorbing fat mass after leptin withdrawal .
the increase in insulin sensitivity when off leptin was clinically evident when the adult male developed severe hypoglycemia during an oral glucose tolerance test .
euglycemic hyperinsulinemic clamps of leptin - deficient patients while on leptin and after brief periods of leptin withdrawal ( from paz - filhoet al . ) .
glucose infusion rates increased in eight out of nine times when leptin therapy was briefly interrupted .
leptin and insulin share common effects in the control of food intake and energy metabolism . in the blood glucose homeostasis ,
leptin and insulin directly regulate each other : 0 leptin inhibits insulin ; insulin stimulates leptin synthesis and secretion .
leptin also increases insulin sensitivity , not only by decreasing adiposity and lipotoxicity , but also insulin - independent action , both centrally and peripherally .
leptin also decreases hepatic production of glucose , contributing to its glucose - lowering effects .
the bone , through osteocalcin , also plays a role in regulating the glucose - insulin homeostasis [ figure 2 ] .
leptin activates the sympathetic tonus , which inhibits insulin secretion and stimulates esp expression in the osteoblast ( via stimulation of the adrenergic beta 2 receptor ) .
insulin , in turn , stimulates leptin expression in the white adipose tissue . adapted from kieffer and habener .
h : hypothalamus in leptin - deficient humans , leptin therapy has been shown to determine remarkable effects , by increasing insulin sensitivity on the long term , by decreasing insulinemia , and ultimately by reversing type 2 diabetes in one previously diabetic patient . in lipodystrophic patients
however , no clinically evident benefits have been observed in patients with type 2 diabetes .
the effects of metreleptin in patients with type 1 diabetes are currently being evaluated in a clinical trial ( clinicaltrials.gov identifier nct01268644 ) . for the development of leptin - based therapies for treating diabetes and disorders that present insulin resistance ,
further human studies need to elucidate the effects of leptin on the glucose - insulin homeostasis , both in the leptin - sensitive and in the leptin - resistant milieus .
 glucose homeostasis is closely regulated not only by insulin , but also by leptin . 
 both hormones act centrally , regulating food intake and adiposity in humans . 
 leptin has several effects on the glucose - insulin homeostasis , some of which are independent of body weight and adiposity . 
 those effects of leptin are determined centrally in the hypothalamus and peripherally in the pancreas , muscles and liver . 
 leptin has beneficial effects on the glucose - insulin metabolism , by decreasing glycemia , insulinemia and insulin resistance . 
 the understanding of the effects of leptin on the glucose - insulin homeostasis will lead to the development of leptin - based therapies against diabetes and other insulin resistance syndromes . in these review , we summarize the interactions between leptin and insulin , and their effects on the glucose metabolism . 
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