Drug Insight: the role of leptin in human physiology and pathophysiology—emerging clinical applications

  title={Drug Insight: the role of leptin in human physiology and pathophysiology—emerging clinical applications},
  author={Aoife M Brennan and Christos S. Mantzoros},
  journal={Nature Clinical Practice Endocrinology \&Metabolism},
  • A. Brennan, C. Mantzoros
  • Published 1 June 2006
  • Biology, Medicine
  • Nature Clinical Practice Endocrinology &Metabolism
Leptin is an adipocyte-secreted hormone with a key role in energy homeostasis. Studies in animal models, in humans with congenital complete leptin deficiency, and observational and interventional studies in humans with relative leptin deficiency (lower than normal leptin levels) have all indicated that leptin regulates multiple physiological functions, primarily in states of energy deficiency. This information led to proof-of-concept clinical trials involving leptin administration to… 

Leptin in human physiology and therapeutics

Leptin in human physiology and pathophysiology.

Understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics is increased, and another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers.

Leptin in reproduction

Recent proof-of-concept studies involving leptin administration to humans underline the critical role of leptin not only in regulating energy homeostasis, but also in maintaining normal reproductive function and suggest a role for leptin as a novel therapeutic approach in several disease states.

Leptin Dysfunction: A Cause for Obesity.

High prevalence of obesity and the numerous negative health effects that are associated with this phenotype, it is relevant to examine the pathway of leptin in order to determine effective treatment

Pathophysiological role of leptin for human health: A review

Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital leptin deficiency, lipoatrophy and women with hypothalamic amenorrhea reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions.

Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine?

New insight is provided into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.

Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals.

Experimental evidence suggests a null or a possibly adverse role of leptin treatment in nonlipodystrophic patients with nonalcoholic fatty liver disease and insights into the emerging clinical applications and therapeutic uses of leptin in humans with lipodystrophy and/or diabetes are provided.

Leptin in Relation to the Lipodystrophy-Associated Metabolic Syndrome

  • C. Mantzoros
  • Medicine, Biology
    Diabetes & metabolism journal
  • 2012
The results of leptin treatment in leptin replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action.

Leptin: a novel therapeutic strategy for Alzheimer's disease.

Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer's disease at the molecular and physiological level and chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models.



Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency.

The wide range of phenotypic abnormalities seen in the leptin-deficient ob/ob mouse and their reversibility by leptin administration provide compelling evidence for the existence of multiple

Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults.

Leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior.

The Role of Leptin in Human Obesity and Disease: A Review of Current Evidence

  • C. Mantzoros
  • Biology, Medicine
    Annals of Internal Medicine
  • 1999
The current understanding of leptin's role in various physiologic and pathophysiologic states in humans is presented and the potential therapeutic implications of the authors' advancing knowledge on energy homeostasis and body weight regulation are discussed.

Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy.

Leptin replacement improved menstrual abnormalities and low E2 levels and corrected the attenuated LH response to LHRH in a group of young women with lipodystrophy and leptin deficiency, adding to the growing body of evidence that metabolic signals such as leptin play a role in neuroendocrine regulation.

A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction

A homozygous mutation in the human leptin receptor gene results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains, which indicates that leptin is an important physiological regulator of several endocrine functions in humans.

Role of leptin in the neuroendocrine response to fasting

It is proposed that regulation of the neuroendocrine system during starvation could be the main physiological role of leptin, and preventing the starvation-induced fall in leptin with exogenous leptin substantially blunts the changes in gonadal, adrenal and thyroid axes in male mice, and prevents the starve-induced delay in ovulation in female mice.

Long-term efficacy of leptin replacement in patients with generalized lipodystrophy.

R-metHuLeptin led to significant and sustained improvements in glycemia, dyslipidemia, and hepatic steatosis and represents the first novel, effective, long-term treatment for severe forms of lipodystrophy.

Effects of recombinant leptin therapy in a child with congenital leptin deficiency.

The administration of leptin corrects their obesity by reducing their food intake and increasing their energy expenditure and these mice also have hyperinsulinemia, corticosterone excess, and infertility, which also are reversed by treatment with leptin.

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.

Three interventional studies involving administration of recombinant methionyl human leptin to lean, otherwise healthy obese, and obese diabetic subjects investigate whether increasing circulating leptin levels over a wide spectrum of values would alter serum levels of inflammatory markers and other cytokines important in the T helper cell response.