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 are prescribed at a high rate for treatment of obesity and diabetes due to their potent effects on lowering bodyweight and improving glucose homeostasis. However, many patients do not stay on incretin analog therapy and thereby rapidly regain bodyweight. The non-compliance of patients to incretin analog therapy is not only due to drug shortage but also insufficient knowledge on 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 therapy withdrawal, mice displayed rapid bodyweight regain, impaired adipose tissue function, and glucose intolerance. In contrast, a 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. To check which genes remain deregulated and which genes are restored upon incretin analog treatment, we performed RNA seq analysis in subcutaneous white adipose tissue (sWAT) obtained from ND-fed mice, HFD-fed mice, HFD-fed mice treated with semaglutide, HFD-fed mice treated with tirzepatide and HFD-fed mice that received a dietary intervention (diet switch from HFD to ND). 8 samples from each group were sequenced, making a total of 40 samples.