Hypothalamic Melanin-Concentrating Hormone and Estrogen-Induced Weight Loss

Abstract

Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide produced by neurons of the lateral hypothalamic area (LHA). Because genetic MCH deficiency induces hypophagia and loss of body fat, we hypothesized that MCH neurons may represent a specific LHA pathway that, when inhibited, contributes to the pathogenesis of certain anorexia syndromes. To test this hypothesis, we measured behavioral, hormonal, and hypothalamic neuropeptide responses in two models of hyperestrogenemia in male rats, a highly reproducible anorexia paradigm.Whereas estrogen-induced weight loss engaged multiple systems that normally favor recovery of lost weight, the expected increase of MCH mRNA expression induced by energy restriction was selectively and completely abolished. These findings identify MCH neurons as specific targets of estrogen action and suggest that inhibition of these neurons may contribute to the hypophagic effect of estrogen.Key words: MCH; estrogen; body weight; energy balance; lateral hypothalamus; anorexia; pair-feedingThe lateral hypothalamus plays a critical role in the regulation of energy intake and expenditure. Initial work performed Ͼ50 years ago demonstrated that bilateral lesions of the lateral hypothalamic area (LHA) result in profound hypophagia in rodents (Stellar, 1954), and recent progress has begun to identify candidate neuronal subpopulations that may mediate these LHA feeding effects. Neurons producing melanin concentrating hormone (MCH) represent one such subset. In rats and mice, intracerebroventricular administration of MCH induces hyperphagia, whereas MCH deficiency induced by targeted gene deletion leads to a hypophagia syndrome and loss of body fat (Qu et al., 1996;Shimada et al., 1998;. Thus, selective inhibition of MCH neurons might be expected to induce an anorexic response.Converging evidence suggests that the hypothalamic arcuate nucleus (ARC), in addition to the LHA, plays a key role in the transduction of peripheral signals reflecting negative energy balance into behavioral, autonomic, and metabolic responses that favor the recovery of lost weight Schwartz et al. 2000). Accordingly, hormonal responses to negative energy balance (declining plasma levels of insulin and leptin in concert with increasing levels of corticosterone) induce the ARC to increase biosynthesis and release of the coexpressed orexigenic molecules neuropeptide Y (NPY) and agouti-related protein (AgRP) and to decrease expression of proopiomelanocortin (POMC), the precursor of the anorexic melanocortin ␣-MSH (Schwartz et al., 1997;Hahn et al., 1998;Havel et al. 2000). Changes in the release of these neuropeptides from ARC neurons are hypothesized to influence energy homeostasis via effects on "second order" neurons situated in adjacent hypothalamic areas, such as the LHA and the paraventricular nucleus (PVN) (Broberger et al., 1998;Elias et al., 1998;Sawchenko, 1998). The abundance of ARC projections to MCH neurons in the LHA (Elias et al., 1998) supports the hypothesis that the MCH system lies "downstream" of ARC ...

Hypothalamic neuropeptide expression following chronic food restriction in sedentary and wheel-running rats

“…Therefore, factors other than energy status may play a more important role in regulating neuropeptides in second-order neurons in the LHA. For instance, MCH expression is inhibited by oestrogen (Murray et al 2000, Mystkowski et al 2000.…”

Neurochemical phenotype of hypothalamic neurons showing Fos expression 23 h after intracranial AgRP

“…MCH knockout mice are hypophagic and lean (57), whereas MCH overexpression causes hyperphagia, obesity, and insulin resistance (39) and intracerebroventricular MCH injections acutely increase food intake (53). On the basis of observations in models of estrogen-induced anorexia in male rats (47), it was suggested that under conditions of food restriction, estrogen acts to inhibit lateral hypothalamic MCH neurons receiving excitatory input from medial hypothalamic NPY neurons. Because ARC NPY neurons coexpress AgRP, it could have been expected that exogenous AgRP would stimulate lateral hypothalamic MCH neurons.…”

Tamoxifen-Induced Anorexia Is Associated With Fatty Acid Synthase Inhibition in the Ventromedial Nucleus of the Hypothalamus and Accumulation of Malonyl-CoA

“…All experiments were conducted in accordance with Home Office Guidelines and the Ethics Committee of the University of Santiago de Compostela. Male rats were used to exclude the confounding effects of the estrous cycle on food intake (22,23). Subcutaneous TMX treatment.…”