Effect of Metformin on Short-Term High-Fat Diet-Induced Weight Gain and Anxiety-Like Behavior and the Gut Microbiota

The pathogenic factors of the complex epidemic disorder–obesity, have expanded from genetic background, endocrine factors, abnormal feeding behaviors, and direct neural control of adipose tissue physiology. As a chronic metabolic disease, it is important to find new potential therapeutic targets and locate a sensitive time window for intervention. In this study, we focus on the early stage of a high-fat diet mouse model: a short-term 3-week treatment. Our results showed that this short-term 3-week HFD can already induce significant body weight gain, increased adipocyte size and surprisingly, anxiety-like behavior of the animals. Then we tried the early intervention with metformin, already reported for its effects in long-term HFD induced obesity. For a short-term 3-week co-treatment, metformin alleviated the HFD-induced increase in body weight, the increase in adipocyte size and furthermore, the anxiety-like behavior. Differences were noted among the normal diet (ND), HFD, and HFD with metformin co-treatment groups in gut microbiota, including its composition and diversity. The possible involvement of gut microbiota cannot be ruled out. Intense phospho-AMPK staining was found in the metformin treatment group in the habenular nuclei, hippocampus and basal ganglia of the brain compared with the HFD group, implying that the anxiolytic effect of metformin could be due to the direct activation of the AMPK pathway in the anxiety-related brain nuclei.