Hypothalamic gene expression profiling in mouse strains susceptible or resistant to diet-induced obesity

摘要

Obesity has developed to a worldwide public health problem. It is caused by a complex disorder of appetite regulation and energy metabolism which are controlled by multiple factors such as genetic predisposition, dietary preferences and life style. The high-fat western-type diet is one of the major factors promoting the development of obesity in the human population. However, not all of the high-fat diet consumers become obese. In this study, two different inbred mouse strains u96 AKR/J and SWR/J were either fed a high-fat diet or standard chow diet. The AKR/J strain represents a mouse model for diet-induced obesity (DIO). Mice of this strain developed obesity when fed a high fat diet, whereas they remained lean on a standard chow. In contrast, mice of the SWR/J strain are resistant to DIO, i.e., there was no discernable increase in body weight or adiposity in mice fed a high fat diet as compared to standard chow. The gene expression arrays were applied to identify differentially expressed genes in the hypothalamus of AKR/J and SWR/J mice in response to high-fat diet feeding. For the candidate genes selected from array data analysis, validation was carried out by northern blot analysis, in situ hybridization and real-time PCR. Hemoglobin alpha, adult chain 1 (Hba-alpha1) is located on mouse chromosome 11 (human chromosome 16p13.3). The functional significance of Hba-alpha1 expression is unclear. Perhaps it facilitates oxygen transport in the brain in a similar manner as myoglobin in muscle. In this study, overall the expression of Hba-alpha1 in brain was higher in SWR/J compared to AKR/J mice. This difference between strains may be related to the fact that SWR/J mice have a higher metabolic rate. So far, no direct relationship between Hba-alpha1 expression and obesity has been suggested. In contrast, Glyoxalase I (Glo 1) shows a very distinct expression pattern with highest levels found in the hippocampus. In the hypothalamus, Glo1 expression can be found in the arcuate nucleus (ARC), ventromedial hypothalamic nucleus (VMH) and paraventricular hypothalamic nucleus (PVN). Whereas the expression of Glo1 outside the hypothalamus is similar in both strains, Glo1 mRNA expression within the hypothalamic region is much stronger in AKR/J compared to SWR/J mice. Glo 1 is located on mouse chromosome 17 (human chromosome 6) and involved in the detoxification of metabolic by-products. It was assigned to the human obesity gene map and has been suggested that aberrant expression of the glyoxalase system is related to cancer and diabetes. Tumor necrosis factor alpha-induced protein 1 (endothelial) (TNFAIP1) is on mouse chromosome 11 (45.10 cM) and human 17q22-q23. The protein functions in potassium ion transport by protein binding and voltage-gated potassium channel activity adjustment. TNFAIP1 localizes in the ARC, the VMH and PVN. It was upregulated by high fat diet in AKR/J mice but not in SWR/J mice, which was shown in filter array and Northern blot but not in real-time RT-PCR and in situ hybridization. In the in situ hybridization, although it showed 1.6 fold upregulation in the ARC and VMH by high fat diet, this difference was not significant because of the individual variation, further experiment with more samples should be carried out to confirm this conclusion. Because it is a newly assigned gene not much information on its pathological relevance is available. So far, there have been no papers linking TNFAIP1 and obesity. However, many publications report on a role of TNFalpha in obesity. It is believed that TNFalpha has an effect on body weight regulation and that it acts probably through a local action on adipose tissue. Possibly, elevated secretion of TNFalpha from adipocytes in obese subjects leads to induction of TNFAIP1 in the hypothalamus. Further research needs to be conducted to elucidate the function of TNFAIP1 in the brain.