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


METHODS
Mice 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.


RESULTS
ArcPomc (-/-) 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.


CONCLUSIONS
Pomc 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.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
Kavaljit H
KH
Chhabra
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.
Jessica M
JM
Adams
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.
Graham L
GL
Jones
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
Miho
M
Yamashita
Lehrstuhl für Biologische Chemie, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising (Weihenstephan), Germany.
Martin
M
Schlapschy
Lehrstuhl für Biologische Chemie, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising (Weihenstephan), Germany.
Arne
A
Skerra
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina.
Marcelo
M
Rubinstein
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: mjlow@umich.edu.
Malcolm J
MJ
Low
Body weight set point; Hypothalamus; Leptin; Leptin resistance; Obesity; PASylation; POMC
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