Potential Role of Central Microglia Activation in High Fat Diet‐Induced Obesity
Authors: Singal Aneesh , Coker Caitlin R. , Bingaman Sarah S. , Arnold Amy C. , Silberman Yuval 
Published: June 2021

Obesity is a leading global health concern that increases risk for Type II diabetes and cardiovascular disease. Obesity is associated with disruptions in insulin sensitivity and glucose homeostasis, increased central and peripheral inflammation, and altered neuronal activity in brain regions controlling food intake and energy expenditure, such as the paraventricular nucleus (PVN) and arcuate nucleus (ARC) of the hypothalamus. For this project, we tested the hypothesis that inhibiting inflammation, via systemic treatment with minocycline, could reduce adverse metabolic consequences associated with high fat diet (HFD)‐induced obesity in mice. We further sought to determine if any metabolic improvements were associated with reduced microglia activity in the hypothalamic PVN or ARC. To test this, 14 male C57Bl/6J mice were given ad libitum access to HFD (60% calories from fat) for 12 weeks. Of these, 8 mice were given minocycline (100 mg/kg, p.o.) during the last 4 weeks of HFD access. Control mice were given standard chow diet (n=6; 10% calories from fat). At the end of treatment, mice underwent intraperitoneal insulin and glucose tolerance tests, followed by immunohistochemistry studies to examine microglia activation in the PVN and ARC, via ionized calcium binding adaptor 1 (Iba‐1) antibody staining. Microglia were separated into ramified (resting glia) versus non‐ramified (active glia) based on size and shape, and the percentage of active microglia (normalized to total microglia number) per region of interest was compared across treatment groups. One‐way ANOVA was used for all group‐wise comparisons. HFD mice had higher body mass compared to control mice (47±1 vs. 31±1 grams; p<0.001). Chronic minocycline treatment significantly attenuated HFD‐induced weight gain (40±1; p<0.001). Minocycline also attenuated the elevated fasting insulin levels in HFD mice (0.8±0.1 chow vs. 4.2±0.9 HFD vs. 2.0±0.2 HFD+minocycline, p<0.01), without effects on fasting glucose levels. HFD mice had significantly reduced insulin sensitivity and glucose tolerance compared to chow mice, which was restored by minocycline treatment. An increased percentage of active microglia was observed in the PVN of HFD mice, and this was prevented by minocycline (44.6±3.9% chow vs. 61.7±4.3% HFD vs. 48.1±3.3% HFD+minocycline, p<0.05). There were no significant effects of either HFD or minocycline on microglia activation in the ARC (44.6±4.3% chow vs. 50.5±5.5% HFD vs. 43.5±4.2% HFD+minocycline, p>0.05). The results of these experiments show that minocycline attenuates weight gain, hyperinsulinemia, insulin resistance, and glucose intolerance in HFD‐induced obese mice. Minocycline treatment is further associated with reduced microglial activation in the PVN but not ARC, illustrating selectivity of anti‐neuroinflammatory effects. Together, these findings suggest that minocycline may improve metabolic function in diet‐induced obesity in part by reducing inflammatory processes in specific subnuclei of the hypothalamus involved in food intake and energy expenditure.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.