The roles of leptin receptors on POMC neurons in the regulation of sex-specific energy homeostasis

Department of Zoology, Miami University, Oxford, OH, United States.
Physiology & Behavior (Impact Factor: 2.98). 02/2010; 100(2):165-72. DOI: 10.1016/j.physbeh.2010.02.018
Source: PubMed


Leptin regulates energy homeostasis and reproduction. One key population of leptin receptors (Lepr) are found on proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus, and evidence links the action of gonadal estrogens to these same POMC neurons. To determine whether Lepr on POMC neurons are critical for reproductive capacity or for sex-specific energy and glucose homeostasis, we studied Cre/loxP mice lacking Lepr specifically on POMC neurons (Pomc-Cre, Lepr(flox/flox) mice) and their controls with normal Lepr (Lepr(flox/flox) mice). Pomc-Cre, Lepr(flox/flox) mice maintained normal reproductive capacity and accumulated more body fat than their same sex controls. Ovariectomy (OVX) was performed to investigate the effects of the estrogens and Lepr on POMC neurons on body fat accumulation and glucose tolerance. OVX Pomc-Cre, Lepr(flox/flox) females accumulated more fat than OVX Lepr(flox/flox) females did. Pomc-Cre, Lepr(flox/flox) males were glucose intolerant and insulin insensitive compared with control males. In contrast, control and Pomc-Cre, Lepr(flox/flox) females had similar glucose tolerance before and after OVX. Therefore leptin's action on POMC neurons reduces body fat accumulation, but is not critical for regulation of reproduction. The sex difference in leptin signaling on POMC neurons on glucose tolerance appears independent of ovarian hormones.

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    • "While 100 µg/Kg STX improves glucose homeostasis in male mice, females are insensitive even after ovariectomy. The lack of effect with STX after ovariectomy suggests that the differences are not due to circulating estrogens, but rather to developmental differences that are not reversed post-ovariectomy, similar to the loss of the leptin receptor in POMC neurons [49]. Gender-specific differences are not uncommon in metabolism. "
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    ABSTRACT: The non-steroidal compound STX modulates the hypothalamic control of core body temperature and energy homeostasis. The aim of this work was to study the potential effects of STX on pancreatic β-cell function. 1-10 nM STX produced an increase in glucose-induced insulin secretion in isolated islets from male mice, whereas it had no effect in islets from female mice. This insulinotropic effect of STX was abolished by the anti-estrogen ICI 182,780. STX increased intracellular calcium entry in both whole islets and isolated β-cells, and closed the K(ATP) channel, suggesting a direct effect on β-cells. When intraperitoneal glucose tolerance test was performed, a single dose of 100 µg/kg body weight STX improved glucose sensitivity in males, yet it had a slight effect on females. In agreement with the effect on isolated islets, 100 µg/kg dose of STX enhanced the plasma insulin increase in response to a glucose load, while it did not in females. Long-term treatment (100 µg/kg, 6 days) of male mice with STX did not alter body weight, fasting glucose, glucose sensitivity or islet insulin content. Ovariectomized females were insensitive to STX (100 µg/kg), after either an acute administration or a 6-day treatment. This long-term treatment was also ineffective in a mouse model of mild diabetes. Therefore, STX appears to have a gender-specific effect on blood glucose homeostasis, which is only manifested after an acute administration. The insulinotropic effect of STX in pancreatic β-cells is mediated by the closure of the K(ATP) channel and the increase in intracellular calcium concentration. The in vivo improvement in glucose tolerance appears to be mostly due to the enhancement of insulin secretion from β-cells.
    PLoS ONE 04/2012; 7(4):e34650. DOI:10.1371/journal.pone.0034650 · 3.23 Impact Factor
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    • "Conditional transgenic knockout approaches have enabled deletion of leptin or insulin receptors from specific neuronal types (e.g. Quennell et al., 2009) but the lack of a strong reproductive phenotype in many of these models (Shi et al., 2010; Donato et al., 2011) suggests that redundancy or developmental compensation may mask the true importance of the pathway. Very recently 'restoration of function' approaches enabled leptin or insulin signalling in one brain region or on one cell type (Donato et al., 2011). "
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    ABSTRACT: Because of the substantial energy demands of reproduction, the brain must temper the fertility of individuals to match nutritional availability. Under-nutrition is associated with infertility in humans and animals. The brain uses adipose- and gut-derived hormones, such as leptin, insulin and ghrelin, to modulate the activity of the GnRH neuronal network that drives reproduction. It is becoming clear that there are both direct and indirect pathways acting on GnRH neurones. A PubMed search was performed using keywords associated with neuropeptides and metabolic hormones that are associated with reproductive and energy balance axes. Evidence that neurones which produce galanin, galanin-like peptide, kisspeptin, alpha-melanocyte-stimulating hormone, neuropeptide Y and oxytocin convey metabolic information to the reproductive axis is presented. The extent to which these neurones express receptors for metabolic hormones is variable but interactions between them allows for complex intermingling of information. Available metabolic fuels modulate hormone input to these neurones, leading in turn to altered GnRH release and appropriate drive to the gonads. The consequent change in sex steroid production is likely to contribute to co-ordination of the network. We hypothesize that the absence of an estrogenic milieu during anovulation compared with presence of estradiol during follicular maturation is important for the regulation of most of the neuropeptides. An improved understanding of the normal responses to energy deprivation may also help to identify novel therapeutic targets for infertility that often accompanies metabolic disorders, such as diabetes, obesity and polycystic ovary syndrome.
    Human Reproduction Update 03/2012; 18(3):313-32. DOI:10.1093/humupd/dms004 · 10.17 Impact Factor
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