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

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-κB 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.