Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity

Abstract

ObjectiveA major challenge for obesity treatment is the maintenance of reduced body weight. Diet-induced obese mice are resistant to achieving normoweight once the obesogenic conditions are reversed, in part because lowered circulating leptin leads to a reduction in metabolic rate and a rebound of hyperphagia that defend the previously elevated body weight set point. Because hypothalamic POMC is a central leptin target, we investigated whether changes in circulating leptin modify Pomc expression to maintain normal energy balance in genetically predisposed obese mice.MethodsMice with reversible Pomc silencing in the arcuate nucleus (ArcPomc−/−) become morbidly obese eating low-fat chow. We measured body composition, food intake, plasma leptin, and leptin sensitivity in ArcPomc−/− mice weight-matched to littermate controls by calorie restriction, either from weaning or after developing obesity. Pomc was reactivated by tamoxifen-dependent Cre recombinase transgenes. Long acting PASylated leptin was administered to weight-reduced ArcPomc−/− mice to mimic the super-elevated leptin levels of obese mice.ResultsArcPomc−/− mice had increased adiposity and leptin levels shortly after weaning. Despite chronic calorie restriction to achieve normoweight, ArcPomc−/− mice remained moderately hyperleptinemic and resistant to exogenous leptin's effects to reduce weight and food intake. However, subsequent Pomc reactivation in weight-matched ArcPomc−/− mice normalized plasma leptin, leptin sensitivity, adiposity, and food intake. In contrast, extreme hyperleptinemia induced by PASylated leptin blocked the full restoration of hypothalamic Pomc expression in calorie restricted ArcPomc−/− mice, which consequently regained 30% of their lost body weight and attained a metabolic steady state similar to that of tamoxifen treated obese ArcPomc−/− mice.ConclusionsPomc reactivation in previously obese, calorie-restricted ArcPomc−/− mice normalized energy homeostasis, suggesting that their body weight set point was restored to control levels. In contrast, massively obese and hyperleptinemic ArcPomc−/− mice or those weight-matched and treated with PASylated leptin to maintain extreme hyperleptinemia prior to Pomc reactivation converged to an intermediate set point relative to lean control and obese ArcPomc−/− mice. We conclude that restoration of hypothalamic leptin sensitivity and Pomc expression is necessary for obese ArcPomc−/− mice to achieve and sustain normal metabolic homeostasis; whereas deficits in either parameter set a maladaptive allostatic balance that defends increased adiposity and body weight.

Persistent effects of obesity: a neuroplasticity hypothesis

“…Hypothalamic proopiomelanocortin-expressing neurons in the arcuate nucleus control energy homeostasis and food intake and may contribute to the determination of body-weight set point. 8 Basal metabolic rates can slow after weight loss, a phenomenon known as metabolic adaptation. 9 Behavioral changes, such as reductions in physical activity, can persist following weight loss, 10 contributing to a reduction in energy expenditure via physical activity.…”

Chronic high prolactin levels impact on gene expression at discrete hypothalamic nuclei involved in food intake

“…Leptin resistance is the leading driver of fat gain in humans, and many experimental models of obesity recapitulate high leptin levels and low brain response to the hormone, possibly triggered by persistent leptin receptor signaling. For example, in high‐fat diet‐induced obesity, in ARN‐ Pomc −/− obese mice and age‐related obesity, an impaired response to leptin was observed. Furthermore, in diet‐induced obesity, a decreased leptin response was observed in the ARN and not in other hypothalamic nuclei such as the DMN and the VMN .…”

POMC-specific knockdown of Tril reduces body adiposity and increases hypothalamic leptin responsiveness

“…The stability of body mass depends on the functional and structural fitness of MBH POMC neurons, as demonstrated by a number of different experimental approaches (11)(12)(13)(14). In humans, mutations of MC4R result in the most common form of monogenic obesity (15,16); in addition, in mutations of POMC, treatment with the MC4R agonist setmelanotide promotes sustainable reduction of hunger and weight (17), providing a clinical proof-ofconcept for the central role of the hypothalamic melanocortin system in the regulation of body mass.…”