Specific inflammatory and mitochondrial signatures characterise the WSB/EiJ mice diet-induced obesity resistance capacity

ABSTRACT Energy balance disruption due to excess of 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. 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 analysed the expression levels of 86 genes related to inflammation and mitochondrial pathways by high throughput microfluidic qPCR on RNA extracted from hypothalamic nuclei of the two strains of mice, under the different HFD treatments. After 3d and 8wk HFD, C57BL/6J mice, in contrast to WSB/EiJ, displayed significantly increased body weight gain, 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 allowed identifying the metabolic pathways involved. Strain-specific differential expression of several individual hypothalamic genes as well as differential effects of HFD between strains reinforced these results. Thus, 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 involvement of the hypothalamic inflammatory and mitochondrial pathways as key factors in the control of energy homeostasis and the resistance to DIO. Highlights Diet-induced-obesity resistance of WSB/EiJ implicates enhanced lipid metabolism WSB/EiJ mice are protected from HFD-induced peripheral and central inflammation Enhanced hypothalamic transport and signalling of endocrine molecules in WSB/EiJ WSB/EiJ hypothalamic mitochondria dynamics differ from C57BL/6J Differential regulation of hypothalamic inflammatory/mitochondria genes in WSB/EiJ