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/jci17490

Cited by 282 publications

(261 citation statements)

References 73 publications

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“…Unlike other hormonal axes [8], however, the fasting-induced decrease in PYY levels is not mediated by falling leptin levels since restoration of leptin levels with exogenous recombinant human leptin administration does not alter the decline in PYY that is associated with acute energy deprivation. Moreover, exogenous administration of recombinant human leptin in doses sufficient to achieve physiological and pharmacological leptin levels does not regulate PYY in the short term, suggesting that, similar to our previous findings on the lack of regulation of ghrelin by leptin [14], the adipocyte-derived leptin and the gut-derived PYY systems act independently of each other.…”

Section: Discussionmentioning

confidence: 89%

“…The first group comprised eight lean men, who were studied during three separate admissions in the GCRC as part of a larger study to evaluate the role of leptin in the neuroendocrine [8] and immune [9] responses to fasting. There was a baseline study on an isocaloric weight-maintaining diet (n=8); a 2-day complete fasting study with administration of placebo (n=8); and a similar fasting study with administration of replacement-dose recombinant human leptin designed to normalise the fasting-induced decline in leptin levels (n=6).…”

Section: Human Subjectsmentioning

confidence: 99%

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Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin

et al. 2005

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Aims/hypothesis: Peptide YY (PYY) is a gutderived hormone that has been shown to reduce short-term food intake in animals and humans. It has been proposed that deficiency of PYY contributes to obesity in humans. However, the physiology of PYY regulation by factors such as caloric restriction, or by other molecules important in energy homeostasis, e.g. leptin, remains to be fully elucidated. Materials and methods: We evaluated the effect on PYY levels of: (1) caloric ingestion (a mixed meal) in five healthy normal-weight subjects; (2) fasting for 2 or 3 days in eight lean men and seven lean women respectively; and (3) recombinant human leptin administration at physiological replacement and pharmacological doses. Results: PYY levels increased 50% after a mixed meal (p=0.01), and shortterm complete fasting for 2 or 3 days decreased leptin and PYY levels to 20-30% and 40-60% of baseline, respectively (both p<0.05). However, recombinant human leptin administration at physiological doses to restore the fasting-induced decrease of leptin levels and at pharmacological doses over the short term had no effect on PYY levels. Conclusions/interpretation: PYY increases after meal ingestion and decreases after fasting in a manner consistent with a meal-related signal of energy homeostasis. Importantly, circulating levels of this gut-secreted molecule are independent of regulation by leptin over the short term. These findings contribute towards our understanding of the homeostatic systems that regulate appetite in humans, including the possible redundancy of gastrointestinally secreted and adipocyte-secreted signals. This may be of importance for the future development of medications to treat obesity.

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Section: Discussionmentioning

confidence: 89%

Section: Human Subjectsmentioning

confidence: 99%

Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin

et al. 2005

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“…Pituitary hormones and bariatric surgery S Camastra et al fasting-induced reduction of TSH secretion in healthy lean men 49 and women. 50 In line with these results, healthy, normal-weight adults the diurnal variation of TSH and leptin secretion are synchronous, suggesting a partial TSH regulation by leptin.…”

Section: Discussionmentioning

confidence: 99%

Daylong pituitary hormones in morbid obesity: effects of bariatric surgery

et al. 2008

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Moderate obesity is known to be associated with multiple endocrine abnormalities. Less information is available on the hormonal status of patients with morbid obesity and on the effects of major weight loss. We studied 16 severely obese (BMI 40.6-69.9 kg/m 2 ) nondiabetic patients and 7 nonobese (BMI range 24.6-27.7 kg/m 2 ), sex-and age-matched healthy volunteers. During 24 h in a metabolic ward, four meals were administered and hourly blood samples were drawn from a central venous catheter for the measurement of glucose, insulin, leptin, thyrotropic hormone (TSH), growth hormone (GH) and prolactin. Insulin sensitivity was measured by a euglycaemic hyperinsulinaemic clamp. Studies were repeated 6 months after biliopancreatic diversion, a mainly malabsorptive surgical approach, which caused an average weight loss of 35±4 kg (or 26 ± 2% of initial weight). Compared with controls, patients were hyperinsulinaemic (290 ± 31 vs 88 ± 4 pmol l À1 , P ¼ 0.0002), insulin resistant (23.5±2.8 vs 52.9±4.9 mmol min À1 kg FFM À1 , P ¼ 0.0006) and hyperleptinaemic (52.5±5.8 vs 10.9±3 ng ml À1 , P ¼ 0.0002). Plasma TSH levels were increased throughout the day-night cycle (averaging 2.02 ± 0.18 vs 1.09 ± 0.19 mU ml À1 of controls, P ¼ 0.01), whereas serum GH levels were suppressed (0.46±0.10 vs 3.01±1.15, P ¼ 0.002). Following surgery, the hyperinsulinaemia and insulin resistance were fully normalized; in concomitance with a major drop in leptin levels (to 14.4±2.7 ng ml À1 , P ¼ 0.02), TSH decreased and GH increased to near-normal levels. In the whole dataset, mean 24-h leptin levels were directly related to mean 24-h TSH levels after controlling for confounders this relationship was lost only after adjusting for fat mass. We conclude that in morbid obesity leptin is a determinant of changes in pituitary function.

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“…38,40 Finally, the significance of leptin in adaptive endocrine and metabolic responses to fasting was demonstrated in healthy subjects. 49 In this study, a replacement dose of recombinant human leptin administered during fasting prevented the starvation-induced changes of endocrine axes.…”

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confidence: 80%

Body weight is regulated by the brain: a link between feeding and emotion

2005

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Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence. Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem. 1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called 'atypical' antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus. [2][3][4] In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin 5 and ghrelin, 6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction. [8][9][10][11][12][13][14] In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to...

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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 282 publications

References 73 publications

Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin

Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin

Daylong pituitary hormones in morbid obesity: effects of bariatric surgery

Body weight is regulated by the brain: a link between feeding and emotion

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