Abstract
Energy imbalance due to excess of calories is considered to be a major player in the current worldwide obesity pandemic and could be accompanied by systemic and central inflammation and mitochondrial dysfunctions. This hypothesis was tested by comparing the wild-derived diet-induced obesity- (DIO-) resistant mouse strain WSB/EiJ to the obesity-prone C57BL/6J strain. We analysed circulating and hypothalamic markers of inflammatory status and hypothalamic mitochondrial activity in both strains exposed to high-fat diet (HFD). We further analysed the regulations of hypothalamic genes involved in inflammation and mitochondrial pathways by high throughput microfluidic qPCR on RNA extracted from laser micro-dissected arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei. HFD induced increased body weight gain, circulating levels of leptin, cholesterol, HDL and LDL in C57BL/6J whereas 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. The gene expression data analysis allowed identifying strain-specific hypothalamic metabolic pathways involved in the respective responses to HFD. Our results point to the involvement of hypothalamic inflammatory and mitochondrial pathways as key factors in the control of energy homeostasis and the resistance to DIO.
Highlights
Energy imbalance due to excess of calories is considered to be a major player in the current worldwide obesity pandemic and could be accompanied by systemic and central inflammation and mitochondrial dysfunctions
high-fat diet (HFD) increased body weight (BW) gain within 3 days in C57BL/6J mice, this effect being reinforced after 8wk challenge (Fig. 1A,B and Table 1)
At the end of treatment, the 8wk group displayed a 6.7% BW increase compared to control animals, resulting in strong BW differences between 12-week old WSB/EiJ and C57BL/6J mice fed with HFD (Fig. 1A and Table 1)
Summary
Energy imbalance due to excess of calories is considered to be a major player in the current worldwide obesity pandemic and could be accompanied by systemic and central inflammation and mitochondrial dysfunctions This hypothesis was tested by comparing the wild-derived diet-induced obesity- (DIO-) resistant mouse strain WSB/EiJ to the obesity-prone C57BL/6J strain. Just one to three days of HFD are sufficient to induce activation of both microglia and astrocytes leading to increased www.nature.com/scientificreports inflammatory markers in the ARC6,7 This hypothalamic inflammation occurs prior to the onset of weight gain and peripheral inflammation, suggesting a neuroprotective response induced by hypothalamic nutrient sensing, rather than adipokines signalling to the hypothalamus. The benefit of using inbred mice to decipher the mechanisms underlying metabolic syndrome has been recently reviewed[13] In this context, we hypothesized that the DIO-resistance observed in WSB/EiJ mice could be centrally regulated via the hypothalamus. Protective mechanisms favouring transport and signalling of endocrine signals could allow for rapid metabolic responses in hypothalamic areas, which should be reflected at the peripheral levels as compared to the C57BL/6J strain
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