Leptin in humans: lessons from translational research
Open accessAbstract
Leptin has emerged over the past decade as a key hormone in not only the regulation of food intake and energy expenditure but also in the regulation of neuroendocrine and immune function as well as the modulation of glucose and fat metabolism as shown by numerous observational and interventional studies in humans with (complete) congenital or relative leptin deficiency. These results have led to proof-of-concept studies that have investigated the effect of leptin administration in subjects with complete (congenital) leptin deficiency caused by mutations in the leptin gene as well as in humans with relative leptin deficiency, including states of lipoatrophy or negative energy balance and neuroendocrine dysfunction, as for instance seen with hypothalamic amenorrhea in states of exercise-induced weight loss. In those conditions, most neuroendocrine, metabolic, or immune disturbances can be restored by leptin administration. Leptin replacement therapy is thus a promising approach in several disease states, including congenital complete leptin deficiency, states of energy deprivation, including anorexia nervosa or milder forms of hypothalamic amenorrhea, as well as syndromes of insulin resistance seen in conditions such as congenital or acquired lipodystrophy. In contrast, states of energy excess such as garden-variety obesity are associated with hyperleptinemia that reflects either leptin tolerance or leptin resistance. For those conditions, development of leptin sensitizers is currently a focus of pharmaceutical research. This article summarizes our current understanding of leptin's role in human physiology and its potential role as a novel therapeutic option in human disease states associated with a new hormone deficiency, ie, leptin deficiency.
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TL;DR
This review synthesizes observational and interventional human studies showing that leptin is a key hormone regulating food intake, energy expenditure, neuroendocrine axes, immune function, and glucose/fat metabolism, with its major physiologic role being to signal inadequate rather than excess energy stores. Leptin replacement therapy restores neuroendocrine, metabolic, and immune function in states of absolute or relative leptin deficiency, whereas states of energy excess (garden-variety obesity) are characterized by hyperleptinemia reflecting leptin tolerance or resistance.
Key findings
- Leptin, a 167-amino acid peptide primarily expressed in adipose tissue, circulates in free (biologically active) form and is secreted in a pulsatile, diurnal-nocturnal pattern; pulse amplitude is higher in obese subjects, while pulsatility characteristics are otherwise similar between lean and obese subjects.
- In congenital leptin deficiency (leptin or leptin receptor mutations), subjects present with hypogonadotropic hypogonadism, low FSH/LH, loss of LH pulsatility, lack of pubertal growth spurt, primary/secondary amenorrhea, growth delay with low IGF-I and IGF-BP3, and hypothalamic hypothyroidism; leptin administration in replacement doses restores these neuroendocrine features and immune function.
- In relative leptin deficiency (hypothalamic amenorrhea, lipoatrophy, anorexia nervosa), r-metHuLeptin in replacement doses restored reproductive function, induced ovulation, increased thyroxine, IGF-I, IGF-BP3, and bone markers, restored GnRH pulsatility, and improved insulin resistance and metabolic profile in HAART-induced lipoatrophy.
- In leptin-sufficient obese subjects with type 2 diabetes, r-metHuLeptin for 4 or 16 wk produced high pharmacologic leptin concentrations but did not activate the TNF-α system or raise cytokines/inflammatory markers above normal, supporting a permissive (not etiopathogenic) role for leptin in immune regulation; placebo-controlled trials in obese persons over 24 wk showed statistically significant but clinically unimpressive weight loss.
Methods
- Narrative review summarizing observational and interventional human studies on leptin physiology and pathophysiology, including pharmacokinetic studies and leptin replacement therapy.
- Evidence drawn from subjects with congenital complete leptin deficiency, leptin receptor mutations, lipoatrophy (congenital/acquired, including HIV/HAART-associated), hypothalamic amenorrhea, anorexia nervosa, and garden-variety obesity, plus healthy normal-weight subjects undergoing fasting/starvation with r-metHuLeptin administration.
- Includes two summary tables: factors regulating circulating leptin concentrations (Table 1) and leptin deficiency/resistance states with estimated prevalences (Table 2), plus a schematic figure of energy deficiency/excess effects on neuroendocrine axes.
Limitations
- Stated: the exact long-term effect of leptin on the hypothalamic-pituitary-GH-IGF axis remains to be fully elucidated; whether resolution of insulin resistance in congenital leptin deficiency is a primary leptin effect or secondary to fat loss/redistribution remains to be clarified; mechanisms of leptin's effects on the thyroid axis are not completely understood; more long-term interventional studies are needed in congenital leptin deficiency; whether r-metHuLeptin alone or combined with other treatments will find a therapeutic place remains to be seen.
- Stated: the role of leptin in the adrenal axis in humans remains controversial, with interventional studies in healthy normal-weight subjects failing to show an effect on adrenal steroids.
- Evident from the text: this is a narrative review without systematic search or meta-analytic synthesis, and several cited findings rest on small proof-of-concept studies; the authors also note their own laboratory received funds from Amgen and Amylin.
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Claims the paper makes
0 of 56 cited sources checked · 0 supported · 0 flagged
- Findingcitation
Leptin concentrations are positively correlated with the amount of body fat.
“Leptin concentrations are positively correlated with the amount of body fat (4-10).”
Quote in the paperSubstantial claim0 of 7 sources checked- cites [4] Brennan, 2007, Leptin and adiponectin: their role in diabetes., Curr Diab Rep source
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- cites [5] Blüher, 2007, Leptin in reproduction., Curr Opin Endocrinol Diabetes Obes source
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- cites [6] Brennan, 2006, Drug insight: the role of leptin in human physiology and pathophysiology: emerging clinical applications in leptin deficient states., Nat Clin Pract Endocrinol Metab source
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- cites [7] Chan, 2006, Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans., Proc Natl Acad Sci USA source
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- cites [8] Kelesidis, 2006, The emerging role of leptin in humans., Pediatr Endocrinol Rev
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- cites [9] Chan, 2005, Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa., Lancet source
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- cites [10] Lee, 2006, Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy., J Clin Endocrinol Metab source
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- Findingcitation
Obese subjects are hyperleptinemic compared with lean persons.
“However, although obese subjects are hyperleptinemic compared with lean persons (11), they appear either to be tolerant or resistant to the central hypothalamic effects of leptin.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Kiess, 2008, Adipocytes and adipose tissue., Best Pract Res Clin Endocrinol Metab source
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- Findingcitation
Children with congenital leptin deficiency are prone to early death as a result of severe infections during childhood because of defects in T cell number and function.
“Children with congenital leptin deficiency are prone to early death as a result of severe infections during childhood because of defects in T cell number and function (28).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Ozata, 1999, J Clin Endocrinol Metab source
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- Findingcitation
Leptin administration improved lipidemia and insulin resistance in HIV-positive patients with partial lipoatrophy.
“It also improved lipidemia and insulin resistance in HIVpositive patients with partial lipoatrophy (10,(22)(23)(24)(25)(26).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Lee, 2006, Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy., J Clin Endocrinol Metab source
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- cites (22)(23)(24)(25)(26)
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- Findingcitation
These disturbances can be completely reversed by leptin administration.
“These disturbances can be completely reversed by leptin administration (6).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Brennan, 2006, Drug insight: the role of leptin in human physiology and pathophysiology: emerging clinical applications in leptin deficient states., Nat Clin Pract Endocrinol Metab source
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- Findingcitation
The clinical features of hypothalamic hypogonadism and associated disturbances can be restored by leptin administration in replacement doses.
“The clinical features of hypothalamic hypogonadism and associated disturbances can be restored by leptin administration in replacement doses (17).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Welt, 2004, Recombinant human leptin in women with hypothalamic amenorrhea., N Engl J Med source
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- Findingcitation
Subjects with mutations of the leptin gene or the leptin receptor gene present with normal adrenal function.
“In contrast to findings in rodents, subjects with mutations of the leptin gene or the leptin receptor gene present with normal adrenal function (16,18).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16] Farooqi, 2007, Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor., N Engl J Med source
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- cites [18] Clement, 1998, A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction., Nature source
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- Findingcitation
Immune function could be markedly improved with leptin replacement.
“However, immune function could be markedly improved with leptin replacement (29,30).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [29] Farooqi, 2002, Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency., J Clin Invest source
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- cites [30] Farooqi, 2008, Monogenic human obesity., Front Horm Res
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- Findingcitation
Leptin administration in replacement doses significantly improved glycemia, dyslipidemia, and hepatic steatosis in lipoatrophic, hypoleptinemic patients with severe insulin resistance.
“It has been shown that leptin administration in replacement doses significantly improved glycemia, dyslipidemia, and hepatic steatosis in lipoatrophic, hypoleptinemic patients with severe insulin resistance.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Lee, 2006, Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy., J Clin Endocrinol Metab source
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- cites (22)(23)(24)(25)(26)
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- Findingcitation
We have not found direct supporting evidence that elevated circulating leptin concentrations directly induce a state of inflammation underlying features of the metabolic syndrome in our interventional studies.
“We have not found direct supporting evidence of this hypothesis in our interventional studies (22).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Chan, 2005, Recombinant methionyl human leptin administration to achieve high physiologic or pharmacologic leptin levels does not alter circulating inflammatory marker levels in humans with leptin sufficiency or excess., J Clin Endocrinol Metab source
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- Findingcitation
r-metHuLeptin administered in replacement doses to healthy subjects after starvation for 72 h prevented the starvation-induced reduction of CD4+CD45RA+ peripheral mononuclear blood cells.
“r-metHuLeptin administered in replacement doses to healthy subjects (after starvation for 72 h) prevented the starvation-induced reduction of CD4 1 CD45RA 1 peripheral mononuclear blood cells (31).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Chan, 2005, J Clin Endocrinol Metab source
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- Findingcitation
In leptin-sufficient obese subjects with type 2 diabetes, administration of r-metHuLeptin for 4 or 16 wk resulted in high pharmacologic leptin concentrations but did not activate the tumor necrosis factor alpha system or increase cytokines or inflammatory markers above the normal range.
“However, in leptin-sufficient obese subjects with type 2 diabetes, the administration of r-metHuLeptin for 4 or 16 wk resulted in high pharmacologic leptin concentrations but did not activate the tumor necrosis factor a system or increase cytokines or inflammatory markers above the normal range.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] Brennan, 2007, Circulating leptin levels are not associated with cardiovascular morbidity and mortality in women with diabetes: a prospective cohort study., Diabetologia source
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- Findingnone given
States of congenital leptin deficiency because of mutations of the leptin gene have been associated with severe obesity, glucose intolerance, and insulin resistance in humans.
“States of congenital leptin deficiency because of mutations of the leptin gene have been associated with severe obesity, glucose intolerance, and insulin resistance in humans.”
Quote in the paperSubstantial claim - Findingcitation
Leptin treatment in children with congenital leptin deficiency results in normalization of several neuroendocrine axes, including the reproductive and thyroid axis, as well as immune function.
“In addition, leptin treatment in children with congenital leptin deficiency results in normalization of several neuroendocrine axes, including the reproductive and thyroid axis, as well as immune function.”
Quote in the paperSubstantial claim - Findingcitation
r-metHuLeptin therapy in replacement doses improved insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by highly active antiretroviral therapy.
“r-metHuLeptin therapy in replacement doses improved insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Lee, 2006, Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy., J Clin Endocrinol Metab source
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- Findingcitation
r-metHuLeptin replacement restored GnRH pulsatility.
“In addition, r-metHuLeptin replacement restored GnRH pulsatility (17), raising thus the intriguing possibility that leptin administration in replacement, physiologic doses could also be a potential treatment of some patients with infertility.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Welt, 2004, Recombinant human leptin in women with hypothalamic amenorrhea., N Engl J Med source
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- Findingcitation
Children with congenital leptin deficiency given leptin have appropriately timed pubertal development.
“These children, when given leptin, have an appropriately timed pubertal development (28,29).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [28] Ozata, 1999, J Clin Endocrinol Metab source
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- cites [29] Farooqi, 2002, Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency., J Clin Invest source
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- Findingnone given
Placebo-controlled trials in obese persons over periods of 24 wk have shown a statistically significant but clinically not impressive weight loss in leptin-treated subjects compared with placebo-treated controls.
“Despite initial hopes, placebo-controlled trials in obese persons over periods of 24 wk have shown a statistically significant but clinically not impressive weight loss in leptin-treated subjects compared with placebo-treated controls.”
Quote in the paperSubstantial claim - Premisereasoning
Leptin regulates neuroendocrine function.
“Leptin has emerged over the past decade as a key hormone in not only the regulation of food intake and energy expenditure but also in the regulation of neuroendocrine and immune function as well as the modulation of glucose and fat metabolism as shown by numerous observational and interventional studies in humans with (complete) congenital or relative leptin deficiency.”
Quote in the paperSubstantial claim - Premisecitation
Deficient leptin signaling because of hyperleptinemia or because of hypo- or aleptinemia caused by mutations of either leptin or the leptin receptor genes results in hyperphagia and decreased energy expenditure in rodents and humans.
“Deficient leptin signaling because of hyperleptinemia (as described above) or because of hypo-or aleptinemia caused by mutations of either leptin or the leptin receptor genes results in hyperphagia and decreased energy expenditure in rodents and humans (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Myers, 2008, Mechanisms of leptin action and leptin resistance., Annu Rev Physiol source
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- Interpretationcitation
Obese subjects appear either tolerant or resistant to the central hypothalamic effects of leptin.
“However, although obese subjects are hyperleptinemic compared with lean persons (11), they appear either to be tolerant or resistant to the central hypothalamic effects of leptin.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [6] Brennan, 2006, Drug insight: the role of leptin in human physiology and pathophysiology: emerging clinical applications in leptin deficient states., Nat Clin Pract Endocrinol Metab source
Not checked in the free run.
- cites [9] Chan, 2005, Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa., Lancet source
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- Premisereasoning
Leptin is a key hormone in the regulation of food intake and energy expenditure.
“Leptin has emerged over the past decade as a key hormone in not only the regulation of food intake and energy expenditure but also in the regulation of neuroendocrine and immune function as well as the modulation of glucose and fat metabolism as shown by numerous observational and interventional studies in humans with (complete) congenital or relative leptin deficiency.”
Quote in the paperSubstantial claim - Premisereasoning
Leptin regulates immune function.
“Leptin has emerged over the past decade as a key hormone in not only the regulation of food intake and energy expenditure but also in the regulation of neuroendocrine and immune function as well as the modulation of glucose and fat metabolism as shown by numerous observational and interventional studies in humans with (complete) congenital or relative leptin deficiency.”
Quote in the paperSubstantial claim - Interpretationreasoning
In conditions of complete or relative leptin deficiency, most neuroendocrine, metabolic, or immune disturbances can be restored by leptin administration.
“In those conditions, most neuroendocrine, metabolic, or immune disturbances can be restored by leptin administration.”
Quote in the paperSubstantial claim - Premisereasoning
Leptin modulates glucose and fat metabolism.
“Leptin has emerged over the past decade as a key hormone in not only the regulation of food intake and energy expenditure but also in the regulation of neuroendocrine and immune function as well as the modulation of glucose and fat metabolism as shown by numerous observational and interventional studies in humans with (complete) congenital or relative leptin deficiency.”
Quote in the paperSubstantial claim - Interpretationcitation
Relative leptin deficiency because of long-term energy deprivation is associated with defects in immunologic variables that may be corrected with exogenous r-metHuLeptin administration.
“Similar to congenital leptin deficiency, relative leptin deficiency because of long-term energy deprivation is associated with defects in immunologic variables that may be corrected with exogenous r-metHuLeptin administration: Leptin replacement therapy alters circulating cytokine concentrations in women with hypothalamic amenorrhea who present with chronic relative leptin deficiency resulting”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [6] Brennan, 2006, Drug insight: the role of leptin in human physiology and pathophysiology: emerging clinical applications in leptin deficient states., Nat Clin Pract Endocrinol Metab source
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- cites [31] Chan, 2005, J Clin Endocrinol Metab source
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- Interpretationreasoning
The major physiologic role of leptin is to signal inadequate rather than excess energy stores.
“However, the major physiologic role of leptin is to signal inadequate rather than excess energy stores.”
Quote in the paperSubstantial claim - Premisecitation
A significant role of leptin in the regulation of the hypothalamic-pituitary-thyroid axis has been well established in humans.
“A significant role of leptin in the regulation of the hypothalamicpituitary-thyroid axis has been well established in humans (6)(7)(8).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [6] Brennan, 2006, Drug insight: the role of leptin in human physiology and pathophysiology: emerging clinical applications in leptin deficient states., Nat Clin Pract Endocrinol Metab source
Not checked in the free run.
- cites [7] Chan, 2006, Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans., Proc Natl Acad Sci USA source
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- cites [8] Kelesidis, 2006, The emerging role of leptin in humans., Pediatr Endocrinol Rev
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- Interpretationcitation
In states of secondary failure of the HPG axis associated with loss of fat mass, such as exercise-induced amenorrhea or anorexia nervosa, exogenously administered leptin may fully normalize function of this axis.
“Moreover, in states of secondary failure of the HPG axis associated with loss of fat mass, such as in exercise-induced amenorrhea or anorexia nervosa, exogenously administered leptin may fully normalize function of this axis (5,7,9,17).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [5] Blüher, 2007, Leptin in reproduction., Curr Opin Endocrinol Diabetes Obes source
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- cites [7] Chan, 2006, Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans., Proc Natl Acad Sci USA source
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- cites [9] Chan, 2005, Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa., Lancet source
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- cites [17] Welt, 2004, Recombinant human leptin in women with hypothalamic amenorrhea., N Engl J Med source
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- Premisecitation
Leptin plays a crucial role in regulating reproduction and the hypothalamic-pituitary-gonadal (HPG) axis.
“Leptin plays a crucial role in regulating reproduction and the hypothalamic-pituitary-gonadal (HPG) axis.”
Quote in the paperSubstantial claim - Interpretationcitation
The role of leptin in regulating immune function appears to be permissive.
“The role of leptin in regulating immune function appears to be a permissive one (33), because there might exist a critical leptin threshold above which leptin has no major additional physiologic effect on neuroendocrine or immune function (7).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [33] Papathanassoglou, 2006, Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice., J Immunol source
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- cites [7] Chan, 2006, Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans., Proc Natl Acad Sci USA source
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- Interpretationnone given
Leptin has been proven to be the adipocyte-secreted hormone that communicates information to several organs about the body's energy reserves.
“During the past decade, leptin has been proven to be the adipocyte-secreted hormone that communicates information to several organs about the body's energy reserves.”
Quote in the paperNot a substantial claim
- May combine two claims. 15
- Classified as probably not a substantial claim. 1
May combine two claims.
FindingcitationSubjects with congenital leptin deficiency or loss of leptin function because of leptin mutations or leptin receptor mutations have clinically evident hypogonadotropic hypogonadism and present with low concentrations of follicle-stimulating hormone and luteinizing hormone, complete loss of luteinizing hormone pulsatility, lack of pubertal growth spurt, reduced expression of secondary sexual traits
“Subjects with congenital leptin deficiency or loss of leptin function because of leptin mutations or leptin receptor mutations have clinically evident hypogonadotropic hypogonadism and present with low concentrations of follicle-stimulating hormone and luteinizing hormone and complete loss of luteinizing hormone pulsatility, lack of pubertal growth spurt, reduced expression of secondary sexual”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Farooqi, 2007, Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor., N Engl J Med source
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May combine two claims.
FindingcitationLeptin administration in replacement doses to healthy lean men during a 3-d starvation period significantly blunted the fasting-induced decrease in TSH pulsatility and increased free thyroxine to concentrations within the normal range.
“Leptin administration in replacement doses to healthy lean men during a 3-d starvation period significantly blunted the fasting-induced decrease in TSH pulsatility and increased free thyroxine to concentrations within 992S the normal range (19).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Chan, 2003, The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men., J Clin Invest source
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FindingcitationAdministering leptin in replacement doses to healthy, normal-weight men after a period of acute fasting partially prevented the decrease in IGF-I and IGF-BP3 but had no short-term effect on circulating concentrations of GH.
“Administering leptin in replacement doses to healthy, normal-weight men after a period of acute fasting that resulted in low IGF-I concentrations partially prevented the decrease in IGF-I and IGF-BP3 but had no (short-term) effect on circulating concentrations of GH (19).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Chan, 2003, The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men., J Clin Invest source
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FindingcitationLeptin-deficient subjects respond dramatically to leptin administered in replacement doses, which induces markedly decreased appetite and food intake and results in a significant reduction in body weight.
“These leptindeficient subjects respond in a dramatic fashion to leptin administered in replacement doses, which induces markedly decreased appetite and food intake and which in turn result in a significant reduction in body weight (28)(29)(30).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [28] Ozata, 1999, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [29] Farooqi, 2002, Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency., J Clin Invest source
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- cites [30] Farooqi, 2008, Monogenic human obesity., Front Horm Res
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May combine two claims.
FindingcitationInterventional studies in women with hypothalamic amenorrhea and low circulating leptin concentrations have proven that r-metHuLeptin in replacement doses may restore reproductive function, induce ovulation, and increase circulating concentrations of thyroxine, IGF-I, IGF-BP3, bone alkaline phosphatase, and other bone markers.
“Interventional studies in women with hypothalamic amenorrhea and low circulating leptin concentrations have proven the concept that r-metHuLeptin in replacement doses may restore reproductive function, induce ovulation, and increase circulating concentrations of thyroxine, IGF-I, IGF-BP3, bone alkaline phosphatase, and other bone markers.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationDeficient leptin signaling results in obesity with increased lipid storage and dysfunction of several neuroendocrine axes, immune and autonomic systems.
“The result is not only an increasing degree of obesity associated with increased lipid storage in muscle, liver, and other tissues but also dysfunction of several neuroendocrine axes, including the reproductive, thyroid, and adrenal axes, as well as abnormal function of the immune and autonomic system (ie, thermoregulation, energy expenditure, and others) (5, 13, 14).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [5] Blüher, 2007, Leptin in reproduction., Curr Opin Endocrinol Diabetes Obes source
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- cites [13] Myers, 2008, Mechanisms of leptin action and leptin resistance., Annu Rev Physiol source
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- cites [14] Blüher S, Mantzoros CS. Insulin resistance in states of energy excess–pathophysiological concepts. In: Mantzoros CS, ed. The metabolic syndrome.Totowa, NJ: Humana Press, in press.
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May combine two claims.
PremisereasoningLeptin is a crucial hormonal factor for regulating several physiologic processes, including inflammation, angiogenesis, hematopoiesis, immune function, and reproduction.
“These findings are consistent with physiology studies, which have proven that leptin is a crucial hormonal factor for regulating several physiologic processes, including inflammation, angiogenesis, hematopoiesis, immune function, and reproduction.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisenone givenStates of energy excess such as garden-variety obesity are associated with hyperleptinemia that reflects either leptin tolerance or leptin resistance.
“In contrast, states of energy excess such as garden-variety obesity are associated with hyperleptinemia that reflects either leptin tolerance or leptin resistance.”
- Also stated in: § ROLE OF LEPTIN IN STATES OF LEPTIN EXCESS · hedged
“Obesity is associated with hyperleptinemia, which may reflect either leptin tolerance or leptin resistance.”
Quote in the paperSubstantial claim- Also stated in: § ROLE OF LEPTIN IN STATES OF LEPTIN EXCESS · hedged
May combine two claims.
InterpretationcitationBoth leptin excess and states of energy deprivation associated with leptin deficiency may increase the individual susceptibility to infection.
“As shown by animal studies as well as observational studies in humans with congential leptin deficiency or obesity-related hyperleptinemia, both leptin excess and states of energy deprivation associated with leptin deficiency may increase the individual susceptibility to infection”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationLeptin has several effects on the innate immune system in leptin-deficient states: it exerts direct effects on macrophages by up-regulating phagocytic activity, stimulates the secretion of proinflammatory cytokines, and stimulates chemotaxis in polymorphonuclear cells.
“Leptin has been shown to have several effects on the innate immune system in leptin-deficient states: It exerts direct effects on macrophages by up-regulating the phagocytic activity, stimulates the secretion of proinflammatory cytokines, and stimulates chemotaxis in polymorphonuclear cells (6).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Brennan, 2006, Drug insight: the role of leptin in human physiology and pathophysiology: emerging clinical applications in leptin deficient states., Nat Clin Pract Endocrinol Metab source
Not checked in the free run.
May combine two claims.
InterpretationcitationLeptin may increase circulating cytokine concentrations and regulate the T helper type 1 and 2 cell immune balance in states of congenital leptin deficiency and immune dysfunction.
“Thus, leptin may increase circulating cytokine concentrations and regulate the T helper type 1 and 2 cell immune balance in states of congenital leptin deficiency and immune dysfunction, supporting a role for leptin in regulating immune function in these conditions (29,30).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [29] Farooqi, 2002, Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency., J Clin Invest source
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- cites [30] Farooqi, 2008, Monogenic human obesity., Front Horm Res
Not checked in the free run.
May combine two claims.
InterpretationcitationInterventional studies show a role for leptin in regulating the immune system in states of leptin deficiency, but not leptin excess as seen in obesity.
“Interventional studies investigating the effect of leptin administration to persons with leptin deficiency compared with leptin sufficiency or leptin excess could clearly show a role for leptin in regulating the immune system in states of leptin deficiency, but not leptin excess, as seen in obesity (22,27,31).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [22] Chan, 2005, Recombinant methionyl human leptin administration to achieve high physiologic or pharmacologic leptin levels does not alter circulating inflammatory marker levels in humans with leptin sufficiency or excess., J Clin Endocrinol Metab source
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- cites [27] Matarese, 2007, Leptin and adipocytokines: bridging the gap between immunity and atherosclerosis., Curr Pharm Des source
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- cites [31] Chan, 2005, J Clin Endocrinol Metab source
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May combine two claims.
Premisenone givenVery rare genetic forms of obesity result from congenital leptin deficiency as a result of mutations in the leptin genes, which are frequently associated with consanguineous marriage.
“Very rare genetic forms of obesity result from congenital leptin deficiency as a result of mutations in the leptin genes, which are frequently associated with consanguineous marriage.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationThese data support a permissive role for leptin in the regulation of the immune system but do not support an etiopathogenic role for leptin in proinflammatory states associated with leptin excess such as obesity.
“These data support a permissive role for leptin in the regulation of the immune system but do not support an etiopathogenic role for leptin in proinflammatory states associated with leptin excess such as obesity (32).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] Brennan, 2007, Circulating leptin levels are not associated with cardiovascular morbidity and mortality in women with diabetes: a prospective cohort study., Diabetologia source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisenone givenLeptin is involved in regulating several neuroendocrine axes, immune function, and glucose and lipid metabolism.
“Subsequent studies have also shown that leptin is involved in regulating several neuroendocrine axes, immune function, and glucose and lipid metabolism.”
Quote in the paperSubstantial claim
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Relative leptin deficiency, such as occurs in congenital or acquired lipodystrophies, thin, very athletic women with hypothalamic amenorrhea, and anorexia nervosa, does respond to leptin administration.
“Relative leptin deficiency, such as occurs in congenital or acquired lipodystrophies, thin, very athletic women with hypothalamic amenorrhea, and anorexia nervosa, does respond to leptin administration 152 153.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [152]
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- Authors
- Blüher, S., & Mantzoros, C. S.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Mantzoros, Christos S
- Venue
- The American Journal of Clinical Nutrition
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 89
- Issue
- 3
- Pages
- 991S-997S
- ISSN
- 0002-9165 (ISSN-L)
- PMC
- PMC2667664
- OpenAlex
- W2085745363
- Semantic Scholar
- 754cc7437a42584ee480fe9f8c45e1cc97089c03
- Cited by
- 203
- References
- 43
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 11 · 2022: 8 · 2021: 12 · 2020: 7 · 2019: 7 · 2018: 3 · 2017: 5 · 2016: 14 · 2015: 19 · 2014: 14 · 2013: 12 · 2012: 27
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal of Clinical Nutrition (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK079929, DK 79929, DK 58785)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- leptin, leptin deficiency, leptin replacement therapy, congenital leptin deficiency, hypothalamic amenorrhea, anorexia nervosa, lipodystrophy, insulin resistance, leptin resistance, obesity, hyperleptinemia, energy balance, food intake regulation, energy expenditure, immune function, glucose metabolism, fat metabolism, neuroendocrine dysfunction
- MeSH terms
- Animals, Humans, Neurosecretory Systems, Leptin
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
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