A dietary intervention following incretin analog treatment restores adipose tissue functions in diet-induced obese mice

Obesity is associated with the development of type 2 diabetes. In recent years, incretin analogs have been prescribed at a high rate for the treatment of obesity and diabetes due to their potent effects on lowering body weight and improving glucose homeostasis. However, many patients do not stay on incretin analog therapy and thereby rapidly regain body weight. The noncompliance of patients to incretin analog therapy is not only due to drug shortage but also insufficient knowledge of the long-term effects of the therapy. To address this knowledge gap, we examined the effects of incretin analog treatment and withdrawal on adipose tissue functions in high-fat diet (HFD)-induced obese mice. Our transcriptome data suggest that incretin analog treatment restored most of obesity-mediated deregulated gene expression in adipose tissue. However, genes encoding lipogenic enzymes, downregulated by HFD, were not restored by incretin analog treatment. Interestingly, a dietary intervention with normal chow diet (ND) feeding, but not calorie-matched HFD feeding, restored the expression of lipogenic enzymes. Upon incretin analog therapy withdrawal, mice displayed rapid body weight regain, impaired adipose tissue function, and glucose intolerance. In contrast, an ND intervention following incretin analog therapy withdrawal restored lipogenic gene expression in adipose tissue, maintained glucose homeostasis, and minimized body weight regain. This study revealed the effects of incretin analog therapy and therapy withdrawal on adipose tissue and highlights the importance of the dietary composition during and after incretin analog therapy. Thus, our findings may contribute to the development of long-term therapy guidelines of incretin analog therapy for patients with obesity.