We searched MEDLINE for articles relating “leptin” to “hypothalamic-pituitary-peripheral axes”, “neuroendocrine function”, “hypothalamic amenorrhea”, “exercise-induced amenorrhea”, and “anorexia nervosa”, with emphasis on articles on human beings.
ReviewRole of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa
Introduction
In 1994, the discovery of leptin fundamentally changed our perspective of adipose tissue from that of an inert energy store to a true endocrine organ that secretes metabolically active hormones. Leptin was identified as the hormone whose absence resulted in morbid obesity in the ob/ob mouse,1 thus acquiring its name from the Greek word “leptos” (thin). Although initially hopes were high that leptin would prove important in the pathophysiology and thus treatment of human obesity, early studies quickly showed that human obesity is generally not associated with leptin deficiency due to a leptin gene defect,2 a finding not altogether surprising in view of the complex, multifactorial nature of obesity. It was also soon realised, however, that leptin might be more important at the other end of the energy homoeostasis spectrum—ie, energy deprivation rather than obesity. In this context, studies in mice3 and also in people4 have shown that leptin has a role in the neuroendocrine adaptation to starvation, which includes changes in hormone concentrations that probably have a protective effect. These findings are clinically relevant for common disease states associated with low leptin concentrations and neuroendocrine abnormalities—ie, energy-deficient states such as exercise-induced amenorrhoea, non-athletic forms of hypothalamic amenorrhoea, and anorexia nervosa. We review the role of leptin in neuroendocrine function, the reproductive and other neuroendocrine abnormalities associated with these energy-deficient conditions, and the evidence that low leptin concentrations could play a part in their pathophysiology and potentially their treatment. We also discuss the clinical relevance of these syndromes with respect to effect on fertility and skeletal health.
Section snippets
Leptin physiology
Leptin is a 167 aminoacid protein product of the ob gene that was discovered in 1994 through positional cloning in the ob/ob obese mouse, a model of morbid obesity resulting from absence of leptin due to a gene mutation.1 The tertiary structure of leptin suggests that it belongs to the cytokine family. Leptin is expressed mainly in white adipose tissue, but also in stomach, placenta, and the mammary gland.5 Leptin circulates in the serum in a free form or bound to leptin-binding proteins, and
Obesity: a high-leptin state
Leptin acts as a signal from the periphery to the brain, conveying information about the amount of energy available in adipose tissue or acute changes in energy availability (or both). Although leptin was originally discovered as an anti-obesity hormone, because congenital absence of leptin causes morbid obesity, the hope that leptin deficiency would play a part in the cause of common obesity in people has not been borne out. Rare cases of functional leptin deficiency due to mutations in the
Hypothalamic-pituitary-gonadal axis
Leptin acts by binding to specific leptin receptor isoforms (one long and several short), which are widely distributed in many tissues.5 The long isoform is expressed abundantly in the hypothalamus and activates mainly the Janus kinase signal transducer and activator of transcription system to change the expression of hypothalamic neuropeptides and thus regulate energy homoeostasis.19, 20 Leptin receptors have also been identified at all levels of this axis, including anterior pituitary,21
Exercise-induced amenorrhoea and other neuroendocrine abnormalities
Menstrual abnormalities arise commonly in association with intensive exercise and athletic sports. The reported frequency of amenorrhoea in female athletes varies widely from a few percent up to 50%, with a positive correlation with training intensity.48, 49, 50 Additionally, independent of training intensity, the type of activity is important with long-distance runners, gymnasts, and ballet dancers (sports that favour a leaner physique) having a particularly high rate of amenorrhoea (40–50%)
Clinical relevance: infertility and osteoporosis
Hypothalamic amenorrhoea is associated with substantial morbidity in terms of fertility and skeletal health. In developed countries, infertility affects 10–20% of couples.115 Infertility is attributable to the female partner in 37% of couples and to both partners in 35%.52 Ovulatory disorders account for 25% of the disease states causing infertility in women, with the most common cause of anovulation being hypothalamic dysfunction (38%).52 At the moment, treatment with injectable gonadotropins
Conclusion and future directions
Much research on leptin, stimulated by intense interest since its discovery in 1994, has transformed and refined our understanding of this molecule. From the initial simplistic view of leptin as an adipocyte-derived hormone that acts in a negative feedback loop with the brain to decrease appetite, we now have a far greater although still incomplete understanding of the pleiotropic nature of this hormone, which affects physiological processes as diverse as neuroendocrine, metabolic, immune, and
Search strategy and selection criteria
References (156)
- et al.
Leptin and reproduction: a review
Fertil Steril
(2002) - et al.
Regulation of in vivo TSH secretion by leptin
Regul Pepts
(2000) - et al.
The in vitro effect of leptin on growth hormone secretion from primary cultured ovine somatotrophs
Endocrine
(2001) Female hypogonadotropic hypogonadism. Hypothalamic amenorrhea syndrome
Endocrinol Metab Clin North Am
(1993)Hypothalamic amenorrhea: clinical perspectives, pathophysiology, and management
Am J Obstet Gynecol
(1990)- et al.
The psychoneuroendocrinology of functional hypothalamic amenorrhea
Psychiatr Clin North Am
(1989) - et al.
Cognitive and psychiatric correlates of functional hypothalamic amenorrhea: a controlled comparison
Fertil Steril
(1993) - et al.
Body composition interpretation. Contributions of the fat-free mass index and the body fat mass index
Nutrition
(2003) - et al.
Altered binding of serum thyroid hormone to thyroxine-binding globulin in women with functional hypothalamic amenorrhea
Fertil Steril
(1997) - et al.
A review of endocrine changes in anorexia nervosa
J Psychiatr Res
(1999)
Plasma concentrations of obese protein in anorexia nervosa
Lancet
Basal metabolic rate in anorexia nervosa: relation to body composition and leptin concentrations
Am J Clin Nutr
Menstrual status and serum leptin levels in anorectic and in menstruating women with low body mass indexes
Fertil Steril
Positional cloning of the mouse obese gene and its human homologue
Nature
Serum immunoreactive-leptin concentrations in normal-weight and obese humans
N Engl J Med
Role of leptin in the neuroendocrine response to fasting
Nature
The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men
J Clin Invest
The role of leptin in human obesity and disease: a review of current evidence
Ann Intern Med
Human leptin levels are pulsatile and inversely related to pituitary-adrenal function
Nat Med
Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects
J Clin Invest
Circadian and ultradian variations of leptin in normal man under continuous enteral nutrition: relationship to sleep and body temperature
J Clin Endocrinol Metab
Effect of fasting on serum leptin in normal human subjects
J Clin Endocrinol Metab
Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro
Diabetes
Leptin: in search of role(s) in human physiology and pathophysiology
Clin Endocrinol.(Oxf)
Sexual dimorphism in plasma leptin concentration
J Clin Endocrinol Metab
Effects of gender, body composition, and menopause on plasma concentrations of leptin
J Clin Endocrinol Metab
A leptin missense mutation associated with hypogonadism and morbid obesity
Nat Genet
Effects of recombinant leptin therapy in a child with congenital leptin deficiency
N Engl J Med
Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects
J Clin Endocrinol Metab
Partial leptin deficiency and human adiposity
Nature
Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial
JAMA
Leptin activation in hypothalamus
Nature
STAT3 signalling is required for leptin regulation of energy balance but not reproduction
Nature
Leptin and leptin receptor expression in rat and mouse pituitary cells
Endocrinology
Expression of functional leptin receptors in the human ovary
J Clin Endocrinol Metab
Expression of leptin receptor in human endometrium and fluctuation during the menstrual cycle
J Clin Endocrinol Metab
In vitro stimulation of the prepubertal rat gonadotropin-releasing hormone pulse generator by leptin and neuropeptide Y through distinct mechanisms
Endocrinology
Expression of a leptin receptor in immortalized gonadotropin-releasing hormone-secreting neurons
Endocrinology
Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin
Nat Genet
Leptin treatment rescues the sterility of genetically obese ob/ob males
Endocrinology
Congenital leptin deficiency is associated with severe early-onset obesity in humans
Nature
A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction
Nature
Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency
J Clin Invest
Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults
Proc Natl Acad Sci USA
Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women
Proc Natl Acad Sci USA
A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty
J Clin Endocrinol Metab
Slowing of pulsatile luteinizing hormone secretion in men after forty-eight hours of fasting
J Clin Endocrinol Metab
Amplitude suppression of the pulsatile mode of immunoradiometric luteinizing hormone release in fasting-induced hypoandrogenemia in normal men
J Clin Endocrinol Metab
Pulsatile intravenous gonadotropin-releasing hormone administration averts fasting-induced hypogonadotropism and hypoandrogenemia in healthy, normal weight men
J Clin Endocrinol Metab
The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin
J Clin Invest
Cited by (297)
Molecular pathways in placental-fetal development and disruption
2024, Molecular and Cellular EndocrinologyPhysical performance during energy deficiency in humans: An evolutionary perspective
2023, Comparative Biochemistry and Physiology -Part A : Molecular and Integrative PhysiologyThe key role of inflammation in the pathogenesis and management of obesity and CVD
2023, Metabolism: Clinical and ExperimentalNovel ketamine and zinc treatment for anorexia nervosa and the potential beneficial interactions with the gut microbiome
2023, Neuroscience and Biobehavioral ReviewsFructose 1-phosphate, an evolutionary signaling molecule of abundancy
2022, Trends in Endocrinology and MetabolismPrimary cilia regulate adaptive responses to fasting
2022, Metabolism: Clinical and Experimental