Molecular physiology of weight regulation in mice and humans. Int J Obes (Lond) 32(Suppl 7):S98-108

Division of Molecular Genetics and Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
International journal of obesity (2005) (Impact Factor: 5). 01/2009; 32 Suppl 7(Suppl. 7):S98-108. DOI: 10.1038/ijo.2008.245
Source: PubMed


Evolutionary considerations relating to efficiency in reproduction, and survival in hostile environments, suggest that body energy stores are sensed and actively regulated, with stronger physiological and behavioral responses to loss than gain of stored energy. Many physiological studies support this inference, and suggest that a critical axis runs between body fat and the hypothalamus. The molecular cloning of leptin and its receptor-projects based explicitly on the search for elements in this axis-confirmed the existence of this axis and provided important tools with which to understand its molecular physiology. Demonstration of the importance of this soma-brain reciprocal connection in body weight regulation in humans has been pursued using both classical genetic approaches and studies of physiological responses to experimental weight perturbation. This paper reviews the history of the rationale and methodology of the cloning of leptin (Lep) and the leptin receptor (Lepr), and describes some of the clinical investigation characterizing this axis.

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    • "While the ICV approach provides unambiguous evidence that leptin can regulate appetite in ruminants, it provides no information on the consequence of reduced central leptin signaling in the normal physiological context. This is an important unresolved issue in the sheep because data in both rodents and humans show that the vast majority of leptin actions are initiated by reduced central signaling (Leibel, 2008). "
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    ABSTRACT: Ruminants remain productive during the energy insufficiency of late pregnancy or early lactation by evoking metabolic adaptations sparing available energy and nutrients (e.g. higher metabolic efficiency and induction of insulin resistance). A deficit in central leptin signaling triggers these adaptations in rodents but whether it does in ruminants remains unclear. To address this issue, five mature ewes were implanted with intracerebroventricular (ICV) cannula in the third ventricle. They were used in two experiments with an ovine leptin antagonist (OLA) when well-conditioned (average body condition score of 3.7 on a 5 point scale). The first experiment tested the ability of OLA to antagonize leptin under in vivo conditions. Ewes received continuous ICV infusion of artificial cerebrospinal fluid (aCSF), ovine leptin (4 g/h) or the combination of ovine leptin (4 g/h) and its mutant version OLA (40 g/h) for 48 h. Dry matter intake (DMI) was measured every day and blood samples were collected on the last day of infusion. ICV infusion of leptin reduced DMI by 24% (P<0.05), and this effect was completely abolished by OLA co-infusion. A second experiment tested whether a reduction in endogenous leptin signaling in the brain triggers metabolic adaptations. This involved continuous ICV infusions of aCSF or OLA alone (40 g/h) for 4 consecutive days. The infusion of OLA did not alter voluntary DMI over the treatment period or on any individual day. OLA did not affect plasma variables indicative of insulin action (glucose, non-esterified fatty acids, insulin and the disposition of plasma glucose during an insulin tolerance test) or plasma cortisol, but tended to reduce plasma triiodothyronine and thyroxine (P<0.07). Overall, these data show that a reduction of central leptin signaling has little impact on insulin action in well-conditioned mature sheep. They also raise the possibility that reduced central leptin signaling plays a role in controlling thyroid hormone production.
    animal 07/2015; -1(11):1-7. DOI:10.1017/S1751731115001159 · 1.84 Impact Factor
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    • "Both obesity and diabetes are consequences of disordered metabolic homeostasis with set points for weight and blood glucose, respectively. In the case of obesity, the set point for weight becomes abnormally high upon weight gain, most likely due to new neuron growth in the hypothalamus [15]. In diabetes, this does not occur. "

    Nutrition 12/2014; 31(1). DOI:10.1016/j.nut.2014.10.002 · 2.93 Impact Factor
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    • "In contrast, 48-h fasted male mice show starvation-induced changes in gonadal, adrenal, and thyroid axes that are all leptin-reversible without significant effect on body weight or on re-feeding after starvation [7]. Taken together, these findings indicate that circulating leptin concentration is a major afferent signal of overall energy availability, and that the hypometabolic phenotype of weight-reduced individuals is the result – at least in part – of a state of perceived relative leptin insufficiency [8]. "
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    ABSTRACT: Circulating leptin concentrations correlate with fat mass and signal the status of somatic energy stores to the brain. Previous studies suggest that diet-induced elevations of body weight increase body weight “set-point”. To assess whether chronic hyperleptinemia is responsible for this shift in defended body weight, we elevated circulating leptin concentrations in lean mice to those comparable to diet-induced obese mice for eighteen weeks. We hypothesized that following cessation of leptin infusion, a higher body weight would be defended. Compared to saline-infused controls, leptin-infused mice had elevated circulating leptin concentrations, gained less weight, yet had similar metabolic rates. Following cessation of leptin administration, leptin-infused mice gained some weight yet plateaued at 5-10% below controls. These results suggest that, unlike mice rendered hyperleptinemic by diet-induced weight gain, leptin-infused mice do not subsequently “defend” a higher body weight, suggesting that hyperleptinemia per se does not mimic the CNS consequences of chronic weight gain.
    Molecular Metabolism 07/2014; 3(4). DOI:10.1016/j.molmet.2014.02.003
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