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) under moderate stretch. the leptin from the mesenchyme, 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. ovulatory cycle in mice, and to a lesser extent in humans, leptin is required for male and female fertility. 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 from the hypothalamus. 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 (severe morning sickness of pregnancy), in polycystic ovary syndrome 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 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 as oestrogen secretion starts during menarche and causes early closure of epiphyses. bone leptin's role in regulating bone mass was identified in 2000. leptin can affect bone metabolism via direct signalling from the brain. leptin decreases cancellous bone, but increases cortical bone. 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 and neurotransmitters) have been found in bone, including adrenaline, noradrenaline, serotonin, calcitonin gene-related peptide, vasoactive intestinal peptide and neuropeptide y. leptin binds to its receptors in the hypothalamus, where it acts through the sympathetic nervous system 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. in terms of both structure and function, leptin resembles il-6 and is a member of the cytokine superfamily. circulating leptin seems to affect the hpa axis, 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, metabolic syndrome, and cardiovascular disease. 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 in a time- and dose-dependent manner.) furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, 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 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. nonsense a nonsense mutation in the leptin gene that results in a stop codon 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 resulting in a reduction of leptin has been observed in two consanguineous 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 gene (q223r, k109r and k656n) and two mutations in the pparg 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, 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 to tyrosine 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. it also is produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (the lower part of the fundic glands), mammary epithelial cells, bone marrow, gastric chief cells and p/d1 cells. diagram representing where leptin is produced in the human body, where it goes, and what it causes 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 (24–72 hours), even when changes in fat mass are not observed. serum level of leptin is reduced by sleep deprivation. leptin levels are paradoxically increased in obesity. leptin level is increased by emotional stress. leptin level is chronically reduced by physical exercise training. leptin level is decreased by increases in testosterone levels and increased by increases in estrogen levels. leptin level is increased by insulin. leptin release is increased by dexamethasone. in obese patients with obstructive sleep apnea, leptin level is increased, but decreased after the administration of continuous positive airway pressure. 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 2+1⁄2-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 leptin and ghrelin on the metabolism control 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, 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, however, deficiency of, or major changes to, the leptin receptor itself are not thought to be a major cause. triglycerides crossing the blood brain barrier (bbb) can induce leptin and insulin resistance in the hypothalamus. triglycerides can also impair leptin transport across the bbb. studies on leptin cerebrospinal fluid (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