Short-term resistance to diet-induced obesity in A/J mice is not associated with regulation of hypothalamic neuropeptides

Abstract

. Shortterm resistance to diet-induced obesity in A/J mice is not associated with regulation of hypothalamic neuropeptides. Am J Physiol Endocrinol Metab 287: E662-E670, 2004; 10.1152/ajpendo.00114.2004.-To investigate the mechanisms underlying long-term resistance of the A/J mouse strain to diet-induced obesity, we studied, over a period of 4 wk, the expression of uncoupling proteins in brown adipose tissue and the expression of hypothalamic neuropeptides known to regulate energy homeostasis and then used microarray analysis to identify other potentially important hypothalamic peptides. Despite increased caloric intake after 2 days of high-fat feeding, body weights of A/J mice remained stable. On and after 1 wk of high-fat feeding, A/J mice adjusted their food intake to consume the same amount of calories as mice fed a low-fat diet; thus their body weight and insulin, corticosterone, free fatty acid, and glucose levels remained unchanged for 4 wk. We found no changes in hypothalamic expression of several orexigenic and/or anorexigenic neuropeptides known to play an important role in energy homeostasis for the duration of the study. Uncoupling protein-2 mRNA expression in brown adipose tissue, however, was significantly upregulated after 2 days of high-fat feeding and tended to remain elevated for the duration of the 4-wk study. Gene array analysis revealed that several genes are up-or downregulated in response to 2 days and 1 wk of high-fat feeding. Real-time PCR analysis confirmed that expression of the hypothalamic IL-1 pathway (IL-1␤, IL-1 type 1 and 2 receptors, and PPM1b/PP2C-␤, a molecule that has been implicated in the inhibition of transforming growth factor-␤-activated kinase-1-mediated IL-1 action) is altered after 2 days, but not 1 wk, of high-fat feeding. The role of additional molecules discovered by microarray analysis needs to be further explored in the future. neuropeptides; energy homeostasis; uncoupling protein-2; interleukin-1; microarray THE EPIDEMIC OF OBESITY in Western populations is associated with overconsumption of high-fat diets. The exact mechanism by which certain people (34) and certain strains of rodents (44) are susceptible to high-fat diet-induced obesity (DIO), whereas others are relatively resistant to its effects, is the subject of intensive investigation.The most thoroughly studied experimental model of DIO is the C57Bl/6J mouse strain, whereas one of the most commonly studied DIO-resistant models is the A/J mouse strain (33, 38 -40). Investigation of the physiological responses of neuroendocrine factors, hypothalamic neuropeptides, and uncoupling proteins (UCPs) to high-fat feeding in these strains of mice could extend our understanding of the pathogenesis of DIO in humans, leading to potentially important therapeutic advances. Although several studies have used the DIO-sensitive C57Bl/6J strain to examine the effect of diet composition on hypothalamic neuropeptides and/or neuroendocrine factors important in energy homeostasis, only one study has focused on the hypothalami...

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