A Missing Link in Body Weight Homeostasis: The Catabolic Signal of the Overfed State

Ravussin, Yann; Leibel, Rudolph L.; Ferrante, Anthony W.

doi:10.1016/j.cmet.2014.09.002

Cited by 95 publications

(112 citation statements)

References 67 publications

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“…The alternative view (consistent with the dual-intervention point model above) is that (low) leptin is a starvation signal and not the adiposity signal at the hub of a lipostatic control system (i.e. a set point) (Ahima et al, 1996;Ravussin et al, 2014;Berthoud et al, 2017;Flier and Maratos-Flier, 2017) If leptin and the canonical hunger signalling pathway in the brain is only the physiological manifestation of the lower intervention point, this suggests there is an as yet unknown physiological system that mediates the upper intervention point that is independent of leptin (see also Ravussin et al, 2014). The existence of such a system is inferred from similar parabiosis experiments that preceded the discovery of leptin.…”

Section: Physiological Consequences Of the Disease-predation Dualintementioning

confidence: 79%

“…In effect, the lack of response to elevated leptin, which is widely interpreted as 'leptin resistance' is not because of some defect in the system, but rather because leptin is only responsible for signalling low fat levels and is not involved in the regulation at the upper intervention point (see also Ravussin et al, 2014). If this idea is correct, the 'problem' of leptin resistance disappears because it is a phenomenon only if one assumes at the outset that there is a setpoint regulation system for adiposity.…”

Section: Physiological Consequences Of the Disease-predation Dualintementioning

confidence: 99%

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The evolution of body fatness: trading off disease and predation risk

Speakman

2018

Journal of Experimental Biology

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Human obesity has a large genetic component, yet has many serious negative consequences. How this state of affairs has evolved has generated wide debate. The thrifty gene hypothesis was the first attempt to explain obesity as a consequence of adaptive responses to an ancient environment that in modern society become disadvantageous. The idea is that genes (or more precisely, alleles) predisposing to obesity may have been selected for by repeated exposure to famines. However, this idea has many flaws: for instance, selection of the supposed magnitude over the duration of human evolution would fix any thrifty alleles (famines kill the old and young, not the obese) and there is no evidence that hunter-gatherer populations become obese between famines. An alternative idea (called thrifty late) is that selection in famines has only happened since the agricultural revolution. However, this is inconsistent with the absence of strong signatures of selection at single nucleotide polymorphisms linked to obesity. In parallel to discussions about the origin of obesity, there has been much debate regarding the regulation of body weight. There are three basic models: the setpoint, settling point and dual-intervention point models. Selection might act against low and high levels of adiposity because food unpredictability and the risk of starvation selects against low adiposity whereas the risk of predation selects against high adiposity. Although evidence for the latter is quite strong, evidence for the former is relatively weak. The release from predation ∼2-million years ago is suggested to have led to the upper intervention point drifting in evolutionary time, leading to the modern distribution of obesity: the drifty gene hypothesis. Recent critiques of the dual-intervention point/ drifty gene idea are flawed and inconsistent with known aspects of energy balance physiology. Here, I present a new formulation of the dual-intervention point model. This model includes the novel suggestion that food unpredictability and starvation are insignificant factors driving fat storage, and that the main force driving up fat storage is the risk of disease and the need to survive periods of pathogen-induced anorexia. This model shows why two independent intervention points are more likely to evolve than a single set point. The molecular basis of the lower intervention point is likely based around the leptin pathway signalling. Determining the molecular basis of the upper intervention point is a crucial key target for future obesity research. A potential definitive test to separate the different models is also described.

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Section: Physiological Consequences Of the Disease-predation Dualintementioning

confidence: 79%

Section: Physiological Consequences Of the Disease-predation Dualintementioning

confidence: 99%

The evolution of body fatness: trading off disease and predation risk

Speakman

2018

Journal of Experimental Biology

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“…Such “controls” are technically difficult and would introduce other confounds, but these concerns are relevant to the interpretation of these studies. Finally, for regions in which leptin-induced STAT3 phosphorylation levels do not fluctuate in proportion to weight gain or loss, secretion of molecules other than leptin from adipose or other tissues could modulate the ability of individual brain regions to respond to leptin [46]. …”

Section: Discussionmentioning

confidence: 99%

Weight Perturbation Alters Leptin Signal Transduction in a Region-Specific Manner throughout the Brain

et al. 2017

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Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin in 4 different groups of weight- and/or diet-perturbed mice. Responses to leptin were assessed by quantifying pSTAT3 levels in brain nuclei 30 minutes following 3 mg/kg intraperitoneal leptin. HFD attenuated leptin sensing throughout the brain, but weight loss did not restore central leptin signaling to control levels in several brain regions important in energy homeostasis, including the arcuate and dorsomedial hypothalamic nuclei. Effects of diet on leptin signaling varied by brain region, with results dependent on the method of weight loss (restriction of calories of HFD, ad lib intake of standard mouse chow). High fat diet attenuates leptin signaling throughout the brain, but some brain regions maintain their ability to sense leptin. Weight loss restores leptin sensing to some degree in most (but not all) brain regions, while other brain regions display hypersensitivity to leptin following weight loss. Normal leptin sensing was restored in several brain regions, with the pattern of restoration dependent on the method of weight loss.

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“…Whether the inadequacy of hyperleptinaemia to correct obesity reflects a diet-induced defect in leptin action or whether the predominant physiological role of leptin is to defend against reductions in body fat remains a topic of discussion and ongoing investigations [20,21]. Separately from this debate, a growing body of evidence supports the thinking that distinct pharmacological interventions can act as applicable leptin sensitisers in the obese leptin-resistant state (see Text box).…”

Section: Targeting Leptin Responsiveness With Pharmacologymentioning

confidence: 99%

Renaissance of leptin for obesity therapy

et al. 2016

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Diet-induced obesity and its metabolic comorbidities constitute an overwhelming health crisis and there is an urgent need for safe and effective pharmacological interventions. Being largely shelved for decades, scientists are now revisiting the antiobesity virtues of leptin. Whereas it remains evident that leptin as a stand-alone therapy is not an effective approach, the potential for employing sensitising pharmacology to unleash the weight-lowering properties of leptin has injected new hope into the field. Fascinatingly, these leptin-sensitising agents seem to act via distinct metabolic pathways and may thus, in parallel with their clinical development, serve as important research tools to progress our understanding of the molecular, physiological and behavioural pathways underlying energy homeostasis and obesity pathophysiology. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium

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A Missing Link in Body Weight Homeostasis: The Catabolic Signal of the Overfed State

Cited by 95 publications

References 67 publications

The evolution of body fatness: trading off disease and predation risk

The evolution of body fatness: trading off disease and predation risk

Weight Perturbation Alters Leptin Signal Transduction in a Region-Specific Manner throughout the Brain

Renaissance of leptin for obesity therapy

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