Resistance to diet-induced obesity is associated with increased proopiomelanocortin mRNA and decreased neuropeptide Y mRNA in the hypothalamus.

Mechanisms mediating genetic susceptibility to diet-induced obesity have not been completely elucidated. Elevated hypothalamic neuropeptide Y (NPY) and decreased hypothalamic proopiomelanocortin (POMC) are thought to promote the development and maintenance of obesity. To assess the potential role of hypothalamic neuropeptide gene expression in diet-induced obesity, the present study examined effects of a high-fat diet on hypothalamic NPY and POMC mRNA in three strains of mice that differ in susceptibility to develop diet-induced obesity. C57BL/6J, CBA, and A/J mice were fed either normal rodent chow or a high-fat diet for 14 weeks after which hypothalamic gene expression was measured. On the high-fat diet, C57BL/6J mice gained the most weight, whereas A/J mice gained the least weight. On the high-fat diet, NPY mRNA significantly decreased as body weight increased in CBA and A/J mice, but not in C57BL/6J mice. In addition, POMC mRNA significantly increased as body weight increased in A/J mice, but not in CBA and C57BL/6J mice. Since decreased NPY mRNA and increased POMC mRNA would presumably attenuate weight gain, these results suggest that a high-fat diet produces compensatory changes in hypothalamic gene expression in mice resistant to diet-induced obesity but not in mice susceptible to diet-induced obesity.

Hyperphagia and weight gain after gold-thioglucose: relation to hypothalamic neuropeptide Y and proopiomelanocortin.

Genetic obesity is associated with increased neuropeptide Y (NPY) messenger RNA (mRNA) and decreased POMC mRNA in the hypothalamus of ob/ob and db/db mice, or impaired sensitivity to alphaMSH (derived from POMC) in the yellow agouti mouse. Acquired obesity can be produced by chemically lesioning the hypothalamus with either monosodium glutamate (MSG) in neonates or gold thioglucose (GTG) in adult mice. The present study examined whether elevated NPY mRNA and/or decreased POMC mRNA in the hypothalamus are associated with obesity due to hypothalamic lesions. GTG injection into adult mice produced a profound obese phenotype, including hyperphagia, increased body weight, and increased leptin mRNA and peptide, in association with reduced hypothalamic NPY mRNA and POMC mRNA. MSG treatment produced virtual elimination of NPY mRNA in the arcuate nucleus and a reduction of hypothalamic POMC mRNA, and led to elevated leptin. MSG pretreatment did not attenuate GTG-induced hyperphagia and obese phenotype. These results do not support a role for NPY-synthesizing neurons in the arcuate nucleus in mediating hypothalamic acquired obesity, but are consistent with the hypothesis that decreased activity of hypothalamic neurons synthesizing POMC play a role in mediating hypothalamic obesity.

Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and [corrected] in ob/ob and db/db mice, but is stimulated by leptin.

Reduction in the activity of the alpha-melanocyte-stimulating hormone (alpha-MSH) system causes obesity, and infusions of alpha-MSH can produce satiety, raising the possibility that alpha-MSH may mediate physiological satiety signals. Since alpha-MSH is coded for by the pro-opiomelanocortin (POMC) gene, we examined if POMC gene expression would be inhibited by fasting in normal mice or in models of obesity characterized by leptin insufficiency (ob/ob) or leptin insensitivity (db/db). In wild-type mice, hypothalamic POMC mRNA was decreased > 60% after a 2-day fast and was positively correlated with leptin mRNA. Similarly, compared with controls, POMC mRNA was decreased by at least 60% in both db/db and ob/ob mice. POMC mRNA was negatively correlated with both neuropeptide Y (NPY) and melanin-concentrating hormone (MCH) mRNA. Finally, treatment of both male and female ob/ob mice with leptin stimulated hypothalamic POMC mRNA by about threefold. These results suggest that impairment in production, processing, or responsiveness to alpha-MSH may be a common feature of obesity and that hypothalamic POMC neurons, stimulated by leptin, may constitute a link between leptin and the melanocortin system.