Caloric Restriction Alleviates Anxiety-Like Behaviors by Mitigating Neuroinflammation and Insulin Signaling Dysregulation in a High-Fat Diet-Induced Obesity Mouse Model.

Abstract

BACKGROUND: Caloric restriction (CR) is reported to promote longevity and improve metabolism in different species, such as rodents and flies. However, limited studies have examined the effects of CR on obesity-associated psychiatric disorders and the underlying mechanisms. OBJECTIVES: This study aimed to investigate the effects of CR on obesity-associated anxiety-like behavior in mice fed on a high-fat diet (HFD) and elucidate the underlying mechanisms. METHODS: Male C57BL/6 mice (n = 24) were randomized into the standard diet group and the HFD group (fed on an HFD for 8 wk to induce obesity). The mice in the HFD group (n = 16) were further randomized into the following 2 groups for an additional 4-wk dietary intervention: the HFD group and calorie-restricted HFD (HFCR) group (received 70% of the mean daily food intake in the previous 3 d). Mouse body weight, anxiety-like behaviors, peripheral insulin sensitivity, central insulin signaling, and fecal microbiota were assessed. RESULTS: HFCR effectively mitigated HFD-induced weight gain and insulin resistance, demonstrating significant reductions in final body weight (-28.0%), glucose area under the curve (-30.7%), and homeostasis model assessment of insulin resistance index (-58.8%) compared with the HFD group (P < 0.01). HFCR also significantly reduced anxiety-like behaviors in open-field and elevated plus maze tests (P < 0.05). Mechanistically, HFCR suppressed neuroinflammatory pathways by inhibiting NF-&#x3ba;B activation and c-Jun N-terminal kinase phosphorylation, while concurrently improving central insulin sensitivity via the insulin receptor substrate 1/Akt pathway (P < 0.05). Furthermore, HFCR remodeled the gut microbiota profile and markedly increased fecal short-chain fatty acid concentrations, with acetic acid and propionic acid levels rising by 107.7% and 57.0%, respectively (P < 0.01). CONCLUSIONS: In summary, our data indicate that CR, even without a change in dietary composition, could attenuate HFD-induced anxiety symptoms by modulating the gut microbiota, suppressing neuroinflammation, and regulating the brain insulin signaling pathway in adult male obese mice.