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...
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_22128778_v5_n10_p869_Chhabra http://hdl.handle.net/20.500.12110/paper_22128778_v5_n10_p869_Chhabra |
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paper:paper_22128778_v5_n10_p869_Chhabra2023-06-08T16:35:16Z Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity Rubinstein, Marcelo Body weight set point Hypothalamus Leptin Leptin resistance Obesity PASylation POMC cre recombinase leptin proopiomelanocortin tamoxifen animal experiment animal model animal tissue anthropometric parameters arcuate nucleus Article body composition body weight set point caloric restriction controlled study energy balance female food intake gene activation gene expression genetic predisposition hormone blood level hormone sensitivity hyperleptinemia hypothalamus low fat diet male metabolic balance metabolic stability morbid obesity mouse nonhuman Pomc gene priority journal steady state transgene weight gain weight reduction 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. © 2016 The Author(s) Fil:Rubinstein, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2016 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_22128778_v5_n10_p869_Chhabra http://hdl.handle.net/20.500.12110/paper_22128778_v5_n10_p869_Chhabra |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Body weight set point Hypothalamus Leptin Leptin resistance Obesity PASylation POMC cre recombinase leptin proopiomelanocortin tamoxifen animal experiment animal model animal tissue anthropometric parameters arcuate nucleus Article body composition body weight set point caloric restriction controlled study energy balance female food intake gene activation gene expression genetic predisposition hormone blood level hormone sensitivity hyperleptinemia hypothalamus low fat diet male metabolic balance metabolic stability morbid obesity mouse nonhuman Pomc gene priority journal steady state transgene weight gain weight reduction |
| spellingShingle |
Body weight set point Hypothalamus Leptin Leptin resistance Obesity PASylation POMC cre recombinase leptin proopiomelanocortin tamoxifen animal experiment animal model animal tissue anthropometric parameters arcuate nucleus Article body composition body weight set point caloric restriction controlled study energy balance female food intake gene activation gene expression genetic predisposition hormone blood level hormone sensitivity hyperleptinemia hypothalamus low fat diet male metabolic balance metabolic stability morbid obesity mouse nonhuman Pomc gene priority journal steady state transgene weight gain weight reduction Rubinstein, Marcelo Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity |
| topic_facet |
Body weight set point Hypothalamus Leptin Leptin resistance Obesity PASylation POMC cre recombinase leptin proopiomelanocortin tamoxifen animal experiment animal model animal tissue anthropometric parameters arcuate nucleus Article body composition body weight set point caloric restriction controlled study energy balance female food intake gene activation gene expression genetic predisposition hormone blood level hormone sensitivity hyperleptinemia hypothalamus low fat diet male metabolic balance metabolic stability morbid obesity mouse nonhuman Pomc gene priority journal steady state transgene weight gain weight reduction |
| description |
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. © 2016 The Author(s) |
| author |
Rubinstein, Marcelo |
| author_facet |
Rubinstein, Marcelo |
| author_sort |
Rubinstein, Marcelo |
| title |
Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity |
| title_short |
Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity |
| title_full |
Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity |
| title_fullStr |
Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity |
| title_full_unstemmed |
Reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and Pomc gene expression reverts extreme obesity |
| title_sort |
reprogramming the body weight set point by a reciprocal interaction of hypothalamic leptin sensitivity and pomc gene expression reverts extreme obesity |
| publishDate |
2016 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_22128778_v5_n10_p869_Chhabra http://hdl.handle.net/20.500.12110/paper_22128778_v5_n10_p869_Chhabra |
| work_keys_str_mv |
AT rubinsteinmarcelo reprogrammingthebodyweightsetpointbyareciprocalinteractionofhypothalamicleptinsensitivityandpomcgeneexpressionrevertsextremeobesity |
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1768541916500066304 |