Surviving starvation: essential role of the ghrelin-growth hormone axis

Goldstein, Joseph L.; Zhao, Tong‐Jin; Sherbet, Daniel; Brown, Michael S.

doi:10.1186/1753-6561-6-s3-o7

Cited by 31 publications

(45 citation statements)

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“…Hypoglycemia was the most conspicuous phenotype resulting from the abrogated ghrelin secretion in GC-β 1 AR -/-mice, developing within just a few days of exposure to severe caloric restriction and probably contributing to the pronounced mortality. This protocol, which rapidly and markedly depletes fat stores and emulates a starvation state (28), has the same effect in mice that lack ghrelin (54), GOAT (52, 60), or GHSR (53) and in mice with targeted ghrelin cell degradation (39). However, the reproducibility of this effect and the dependency of ghrelin secretion in this starvation model on ghrelin cell β 1 AR expression were not expected, especially since low glucose can itself stimulate ghrelin secretion (26).…”

Section: Discussionmentioning

confidence: 99%

“…Ex vivo studies with primary cultures of dispersed mouse gastric mucosal cells, approximately 0.3% to 1% of which include ghrelin cells, demonstrate that ghrelin cells can directly sense glucose, enhancing ghrelin release upon exposure to glucose concentrations representative of hypoglycemia and reducing ghrelin release when exposed to high glucose levels (26,27). Not only does exposure of ghrelin cells to low glucose levels stimulate ghrelin release, but increased sympathoadrenal tone, as occurs during the usual counterregulatory response to hypoglycemia, could also stimulate ghrelin secretion (26,28). Supportive of this assertion, ghrelin secretion increases when sympathetic nerves are stimulated artificially or when adrenergic agents are infused locally into the gastric submucosa (29,30).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals

Mani¹,

Osborne-Lawrence²,

Vijayaraghavan³

et al. 2016

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals

Mani¹,

Osborne-Lawrence²,

Vijayaraghavan³

et al. 2016

Journal of Clinical Investigation

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“…Recent studies have demonstrated that the ghrelin-GH axis is central for survival during chronic calorie restriction and that food-restricted mice with genetic deletion of ghrelin or ghrelin O-acyltransferase succumbed due to hypoglycemia (15,16). We therefore tested whether administration of exogenous ghrelin or GH would be able to rescue the lethality of parabiosis of db mice.…”

Section: Resultsmentioning

confidence: 99%

“…hormones central for survival during calorie restriction (15,16). We then set out to biochemically purify leptin-interacting protein(s) from human plasma and showed that ∼25% of leptin circulates in a high-molecular-weight complex.…”

Section: Significancementioning

confidence: 99%

Reanalysis of parabiosis of obesity mutants in the age of leptin

Zeng

Lee

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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In this study we set out to explain the differing effects of parabiosis with genetically diabetic (db) mice versus administration of recombinant leptin. Parabiosis of db mutant, which overexpress leptin, to wildtype (WT) or genetically obese (ob) mice has been reported to cause death by starvation, whereas leptin infusions do not produce lethality at any dose or mode of delivery tested. Leptin is not posttranslationally modified other than a single disulphide bond, raising the possibility that it might require additional factor(s) to exert the maximal appetite-suppressing effect. We reconfirmed the lethal effect of parabiosis of db mutant on WT mice and further showed that this lethality could not be rescued by administration of ghrelin or growth hormone. We then initiated a biochemical fractionation of a high-molecular-weight leptin complex from human plasma and identified clusterin as a major component of this leptin-containing complex. However, in contrast to previous reports, we failed to observe a leptin-potentiating effect of either exogenous or endogenous clusterin, and parabiosis of db clusterin −/− double-mutant to WT mice still caused lethality. Intriguingly, in parabiotic pairs of two WT mice, leptin infusion into one of the mice led to an enhanced starvation response during calorie restriction as evidenced by increased plasma ghrelin and growth-hormone levels. Moreover, leptin treatment resulted in death of the parabiotic pairs. These data suggest that the appetite suppression in WT mice after parabiosis to db mutants is the result of induced hyperleptinemia combined with the stress or other aspect(s) of the parabiosis procedure.eptin functions as an afferent signal in a negative feedback loop that maintains constancy of adipose tissue mass. Leptin acts on its receptors located in the hypothalamus and elsewhere to regulate the neuroendocrine axis, food intake, metabolism, and body weight. The existence of an appetite-suppressing hormone was first suggested by the results from a set of parabiosis experiments between genetically obese (ob) and diabetic (db) mice as well as in studies of the rats with electrolytic lesions of the ventromedial hypothalamus (VMH) that also causes obesity (1-3). The ob and db loci are fully penetrant autosomal-recessive mutations that cause extreme obesity and encode leptin and the leptin receptor, respectively (4, 5).A key finding in these classic parabiosis experiments has been the observation that parabiosis of db mice or VMH-lesioned rats completely suppressed the appetite of wildtype (WT) or ob animals, leading to death by apparent starvation. The parabiotic partners of db mice were reported to be lean and hypoglycemic with little or no food in the stomach (1, 2). These studies suggested that db mice overproduce an endogenous appetite suppressant, and based on these studies, Coleman correctly predicted that the mouse ob gene encoded a novel hormone regulating body weight. The fact that db mice overproduce an appetite suppressant but were obese suggested that this gene ...

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“…For example, at the organismal level, one of the manifestations of an autophagy-like process is fat consumption during starvation, when the organism as a system consumes part of its own structure and redistributes the energy freed from adipose tissue. 7 This process compensates for energy influx oscillation and is vitally important for the organism. Other phenomena, such as placentophagy (consuming of the placenta after delivery in mammals), 9 exuviae eating (eating the old skin after molting in amphibians and insects), 10 or cannibalism in animals, 11 at first glance also seem reminiscent of autophagy.…”

Section: Autophagy Overviewmentioning

confidence: 99%