Reduced central and peripheral inflammatory responses and increased mitochondrial activity contribute to diet-induced obesity resistance in WSB/EiJ mice.

Objectives Energy balance disruption due to excess of calorie-rich food is considered to be one of the major players in the current worldwide obesity pandemic. In rodents, a high fat diet (HFD) induces not only obesity, but also inflammation and mitochondrial dysfunctions. To identify factors underlying diet-induced obesity (DIO) resistance we compared the wild-derived mouse strain WSB/EiJ, characterized by a striking resistance to DIO, with the more DIO-sensitive C57BL/6J strain. Methods We analysed circulating levels of lipids, cytokines and adipokines as well as hypothalamic markers of inflammatory status and mitochondrial activity in both strains exposed to HFD for three days (3d) or eight weeks (8wk). To identify hypothalamic genes potentially involved in these differential regulations, we selected 86 genes related to inflammation and mitochondrial pathways. We analysed their expression levels by high throughput microfluidic qPCR on RNA extracted from laser micro-dissected arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei of the two strains of mice, under the different HFD treatments. Results After 3d and 8wk HFD, C57BL/6J mice, in contrast to WSB/EiJ, displayed significantly increased body weight gain, and also increased circulating levels of leptin, cholesterol, HDL and LDL. WSB/EiJ mice displayed a lower inflammatory status, both peripherally (lower levels of circulating cytokines) and centrally (less activated microglia in the hypothalamus) as well as more reactive mitochondria in the hypothalamus. Principal Component Analysis and gene ontology analysis of gene expression data showed, first, that datasets segregated as a function of strain and second, allowed to identify the metabolic pathways involved. These results were reinforced by the identification of strain specific differential expression of several individual hypothalamic genes as well as differential effects of HFD between strains. Conclusions Adaptation to metabolic stress in the DIO-resistant WSB/EiJ strain implicates enhanced lipid metabolism, lower peripheral and hypothalamic inflammatory status and higher mitochondrial activity than in the C57BL/6J strain. These results point to the implication of the hypothalamic inflammatory and mitochondrial pathways as key factors in the control of energy homeostasis and the resistance to DIO.