Research reportResistance to diet-induced obesity is associated with increased proopiomelanocortin mRNA and decreased neuropeptide Y mRNA in the hypothalamus
Introduction
Since obesity is a classic example of an interaction between environment (e.g., diet) and heredity, it is of great interest to determine the mechanisms which predispose some individuals to become obese on a particular diet, whereas other individuals on the same diet do not become obese. For example, C57BL/6J mice, but not A/J mice, develop obesity when fed a high-fat diet [19]. Differences in susceptibility to develop obesity in response to a nutritional challenge may involve differential regulation of hypothalamic neuropeptides that control energy balance.
In some forms of genetic obesity, hypothalamic neuropeptide Y (NPY) mRNA is elevated, and hypothalamic proopiomelanocortin mRNA (POMC) is reduced 13, 16. In one model of diet-induced obesity, rats prone to diet-induced obesity, but maintained on a chow diet, exhibited elevated levels of NPY mRNA in the arcuate nucleus compared to rats on a chow diet which were resistant to diet-induced obesity [11]. Taken together the evidence suggests that elevated NPY and decreased POMC in the hypothalamus may play a role in promoting the development of obesity.
Based on these studies, it is plausible to raise two opposing hypotheses regarding diet-induced obesity: (i) obesity-prone mice (e.g., C57BL/6J mice) become obese because a high-fat diet produces a primary, obesity-causing effect in them (e.g., elevated NPY mRNA and decreased POMC mRNA) but not in obesity-resistant mice (e.g., A/J mice) or, conversely, (ii) obesity-resistant mice do not become obese because a high-fat diet produces a compensatory anti-obesity effect in them (e.g., decreased NPY and increased POMC mRNA) but not in obesity-prone mice. The first hypothesis predicts that in diet-induced obesity, body weight would be positively correlated with NPY mRNA and negatively correlated with POMC mRNA, as occurs in some forms of genetic obesity 6, 13, 16. In contrast, the second hypothesis predicts that resistance to diet-induced obesity would be associated with a compensatory hypothalamic response (i.e., body weight would be negatively correlated with NPY mRNA and positively correlated with POMC mRNA). In the present study, three strains of mice that differ in susceptibility to develop diet-induced obesity were fed an obesity-producing high-fat diet or a chow diet. We report that the second prediction is observed. These data suggest that resistance to diet-induced obesity is a result of an appropriate compensatory response at the level of the hypothalamus whereas attenuated or impaired hypothalamic compensation in response to a high-fat diet is associated with increased weight gain and obesity.
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Animals
The experimental protocol was approved by the institutional Animal Care Committee. Mature male mice of the C57BL/6J (n=12), CBA (n=12), and A/J (n=9) strains were purchased from Jackson Labs and housed in suspended wire cages in a temperature- (23°C) and light-controlled room (lights on from 0700 h to 1900 h). Mice were allowed free access to food and water unless otherwise noted. One week after arrival the mice were fed either a high-fat, high-simple-carbohydrate diet (diet no. F2685,
Effect of diet on body weight in three strains of mice
There was a differential response to ingestion of a high-fat diet between the three strains of mice. Analysis of variance detected a significant effect of diet (F=116, p<0.0001), strain (F=27.1, p<0.0001), and a strain×diet interaction (F=6.4, p<0.01) on body weight. Ingestion of a high-fat diet resulted in a greater weight gain (i.e., increase in body weight between the start and the completion of the experiment) as compared to chow-fed controls in all three strains. However, there were
Discussion
Obesity is often associated with elevated hypothalamic NPY mRNA and/or decreased hypothalamic POMC mRNA 9, 11, 13, 15, 16, 22. This pattern of hypothalamic gene expression probably contributes to the obese phenotype because (i) infusion of NPY stimulates feeding, and, if carried out chronically, produces obesity 4, 17, 23, 24; (ii) eliminating NPY gene expression attenuates obesity in ob/ob mice [5]; (iii) inactivating mutations in the POMC gene cause obesity [10]; and (iv) eliminating
Acknowledgements
This work was supported by grants from the Manitoba Medical Service Foundation (H.T. Bergen) and the NIH (DK 50110-01; C.V. Mobbs).
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