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Publication
Reprogramming the body weight set point by a reciprocal interaction of
hypothalamic leptin sensitivity and Pomc gene expression reverts extreme
obesity.
Authors Chhabra KH, Adams JM, Jones GL, Yamashita M, Schlapschy M, Skerra A, Rubinstein
M, Low MJ
Submitted By Submitted Externally on 1/10/2022
Status Published
Journal Molecular metabolism
Year 2016
Date Published 10/1/2016
Volume : Pages 5 : 869 - 881
PubMed Reference 27689000
Abstract 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., 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., 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., 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.




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