The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men

Chan, Jean L.; Heist, Kathleen; DePaoli, Alex M.; Veldhuis, Johannes D.; Mantzoros, Christos S.

doi:10.1172/jci200317490

Cited by 543 publications

(311 citation statements)

References 57 publications

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“…In lean healthy subjects, the circadian rhythms of TSH and leptin are superimposable (45), and the subcutaneous administration of leptin significantly blunts the fall of TSH secretion induced by prolonged fasting (46). These findings indicate that leptin has a regulatory effect on TSH secretion.…”

Section: The Leptin-thyroid Relationshipmentioning

confidence: 71%

MECHANISMS IN ENDOCRINOLOGY: The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease

Santini

Marzullo

Rotondi

et al. 2014

European Journal of Endocrinology

204

185

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Obesity and thyroid diseases are common disorders in the general population and they frequently occur in single individuals. Alongside a chance association, a direct relationship between 'thyroid and obesity' has been hypothesized. Thyroid hormone is an important determinant of energy expenditure and contributes to appetite regulation, while hormones and cytokines from the adipose tissue act on the CNS to inform on the quantity of energy stores. A continuous interaction between the thyroid hormone and regulatory mechanisms localized in adipose tissue and brain is important for human body weight control and maintenance of optimal energy balance. Whether obesity has a pathogenic role in thyroid disease remains largely a matter of investigation. This review highlights the complexity in the identification of thyroid hormone deficiency in obese patients. Regardless of the importance of treating subclinical and overt hypothyroidism, at present there is no evidence to recommend pharmacological correction of the isolated hyperthyrotropinemia often encountered in obese patients. While thyroid hormones are not indicated as anti-obesity drugs, preclinical studies suggest that thyromimetic drugs, by targeting selected receptors, might be useful in the treatment of obesity and dyslipidemia.

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Section: The Leptin-thyroid Relationshipmentioning

confidence: 71%

MECHANISMS IN ENDOCRINOLOGY: The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease

Santini

Marzullo

Rotondi

et al. 2014

European Journal of Endocrinology

204

185

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“…Chan et al showed that a period of 72-h fasting in healthy men induces a decrease in serum T 3 by 30%, and a marked suppression of TSH secretion with a decrease in integrated area by over 70% as well as loss of the typical pulsatility characteristics observed in the fed state. Interestingly, administration of a replacement dose of leptin designed to maintain serum leptin at levels similar to those in the fed state largely prevented the starvationinduced changes in the HPT axis (7). In addition to these changes at the central level of the HPT axis during food deprivation, peripheral TH metabolism is also affected by fasting.…”

Section: Feeding Statusmentioning

confidence: 99%

“…However, already in the 1980s, it became clear that a variety of illnesses, including myocardial infarction, sepsis and surgical procedures, cause a decrease in serum triiodothyronine (T 3 ) levels and -in severe cases -T 4 , without an elevation in TSH. Since then, additional examples of exogenous factors (schematically represented in Within the circle, the HPT axis setpoint is driven mainly by TRH physiological factors include the diurnal TSH rhythm with a clear nocturnal TSH surge (6), which is driven by the hypothalamic suprachiasmatic nucleus (SCN), and prolonged fasting, which induces a decrease both in serum T 3 (by 30%) and serum TSH (by 70%) in healthy men (7). By inference, feeding status and time-of-day effects should be considered in careful interpretation of serum TSH in a clinical setting.…”

Section: Introductionmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Beyond the fixed setpoint of the hypothalamus–pituitary–thyroid axis

Fliers

Kalsbeek

Boelen

2014

European Journal of Endocrinology

106

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The hypothalamus-pituitary-thyroid (HPT) axis represents a classical example of an endocrine feedback loop. This review discusses dynamic changes in HPT axis setpoint regulation, identifying their molecular and cellular determinants, and speculates about their functional role. Hypothalamic thyrotropin-releasing hormone neurons were identified as key components of thyroid hormone (TH) setpoint regulation already in the 1980s, and this was followed by the demonstration of a pivotal role for the thyroid hormone receptor beta in negative feedback of TH on the hypothalamic and pituitary level. Gradually, the concept emerged of the HPT axis setpoint as a fixed entity, aiming at a particular TH serum concentration. However, TH serum concentrations appear to be variable and highly responsive to physiological and pathophysiological environmental factors, including the availability or absence of food, inflammation and clock time. During food deprivation and inflammation, TH serum concentrations decrease without a concomitant rise in serum TSH, reflecting a deviation from negative feedback regulation in the HPT axis. Surprisingly, TH action in peripheral organs in these conditions cannot be simply predicted by decreased serum TH concentrations. Instead, diverse environmental stimuli have differential effects on local TH metabolism, e.g. in liver and muscle, occurring quite independently from decreased TH serum concentrations. The net effect of these differential local changes is probably a major determinant of TH action at the tissue level. In sum, hypothalamic HPT axis setpoint regulation as well as TH metabolism at the peripheral organ level is flexible and dynamic, and may adapt the organism in an optimal way to a range of environmental challenges.

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“…Leptin is secreted from adipocytes into the bloodstream in proportion to body fatness, and signals energy sufficiency and acts on the hypothalamus to suppress feeding and increase energy expenditure. Serum leptin concentrations change gradually over time in response to changes in fat mass, but fall rapidly in response to complete fasting (Boden et al 1996, Chan et al 2003, and this fall in leptin concentration is thought to mediate reproductive suppression due to nutritional stress. For example, preventing the starvation-induced fall in leptin with exogenous leptin was shown to prevent the starvation-induced delay in ovulation in female mice (Ahima et al 1996).…”

Section: Leptinmentioning

confidence: 99%

Neuroendocrine integration of nutritional signals on reproduction

Evans

Anderson

2017

Journal of Molecular Endocrinology

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Reproductive function in mammals is energetically costly and therefore tightly regulated by nutritional status. To enable this integration of metabolic and reproductive function, information regarding peripheral nutritional status must be relayed centrally to the gonadotropin-releasing hormone (GNRH) neurons that drive reproductive function. The metabolically relevant hormones leptin, insulin and ghrelin have been identified as key mediators of this 'metabolic control of fertility'. However, the neural circuitry through which they act to exert their control over GNRH drive remains incompletely understood. With the advent of Cre-LoxP technology, it has become possible to perform targeted gene-deletion and gene-rescue experiments and thus test the functional requirement and sufficiency, respectively, of discrete hormone-neuron signaling pathways in the metabolic control of reproductive function. This review discusses the findings from these investigations, and attempts to put them in context with what is known from clinical situations and wild-type animal models. What emerges from this discussion is clear evidence that the integration of nutritional signals on reproduction is complex and highly redundant, and therefore, surprisingly difficult to perturb. Consequently, the deletion of individual hormone-neuron signaling pathways often fails to cause reproductive phenotypes, despite strong evidence that the targeted pathway plays a role under normal physiological conditions. Although transgenic studies rarely reveal a critical role for discrete signaling pathways, they nevertheless prove to be a good strategy for identifying whether a targeted pathway is absolutely required, critically involved, sufficient or dispensable in the metabolic control of fertility.

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The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men

Cited by 543 publications

References 57 publications

MECHANISMS IN ENDOCRINOLOGY: The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease

MECHANISMS IN ENDOCRINOLOGY: The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease

MECHANISMS IN ENDOCRINOLOGY: Beyond the fixed setpoint of the hypothalamus–pituitary–thyroid axis

Neuroendocrine integration of nutritional signals on reproduction

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