Een studie naar de respons van vetweefsel op behandeling van obesitas met incretine analogen

Obesity affects more than 15% of the world population and is associated with the development of glucose intolerance and type 2 diabetes. In recent years, drugs mimicking incretin hormones are prescribed at a high rate for treatment of obesity and diabetes. Incretins such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gut-derived hormones that slow gastric emptying, stimulate insulin secretion and suppress appetite. Thus, incretin analogs have potent effects on lowering body weight and improving glucose homeostasis. The GLP-1 analog semaglutide and GLP-1/GIP dual analog tirzepatide are the most widely used incretin analogs in clinical practice. Semaglutide and tirzepatide cause approximately 15% and 20 % reductions in body weight, respectively, and both drugs improve glucose tolerance and insulin sensitivity. However, recent studies suggest that many patients do not stay on incretin analog therapy and thereby rapidly regain body weight. 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. Adipose tissue is an important insulin-sensitive, energy storing organ and is one of the most affected organs upon obesity. Next to storing lipids, adipose tissue can take up glucose and convert it to lipids via a process called de novo lipogenesis (DNL). Even though the contribution of adipose DNL to body weight is limited, adipose DNL is necessary to maintain whole-body insulin sensitivity and glucose homeostasis. Next to the energy storage function, adipose tissue plays an endocrine role to control whole-body energy homeostasis. For example, adipose tissue suppresses food intake by secreting the hormone leptin. Upon obesity, adipose tissue expands by increasing adipocyte size, which is associated with inflammation and leptin resistance. Obesity also causes impaired adipose function such as decreased adipose DNL, which results in whole-body insulin insensitivity and hyperglycemia. Dietary interventions ameliorate adipocyte hypertrophy, restore adipose DNL and hyperleptinemia. However, it was recently shown that adipose tissue contains an obesogenic memory with certain genes being deregulated even after weight loss. In contrast to dietary interventions, the effects of incretin analogs on adipose tissue at the molecular level remain elusive. To address this knowledge gap and provide a guideline for long-term therapy strategy for obesity, which is currently unavailable in clinical practice, we examined the effects of incretin analog treatment and withdrawal on adipose tissue functions in diet-induced obese (DIO) mice. Transcriptome analysis of subcutaneous white adipose tissue (sWAT) showed that incretin analog treatment restored most of obesity-mediated deregulated gene expression in adipose tissue, including adipose inflammation and leptin resistance. However, genes encoding lipogenic enzymes and some of the deregulated obesogenic memory marker genes, were only restored by weight loss induced by a dietary intervention and not by incretin analog treatment. Importantly, weight loss induced by high-fat diet restriction also did not restore adipose DNL, highlighting the importance of the dietary composition during incretin analog treatment. Upon incretin therapy withdrawal, mice displayed rapid body weight regain and glucose intolerance, impaired adipose tissue function with increased inflammation and hyperleptinemia, and a loss of relative lean mass. In contrast, a dietary intervention following incretin analog therapy withdrawal minimized body weight regain and mice remained glucose tolerant. Moreover, lipogenic gene expression and adipose tissue obesogenic memory marker genes were partially restored. Importantly, a dietary intervention following incretin analog treatment preserved lean mass, which is known to counteract body weight gain and contributes to glucose homeostasis. Altogether, our findings revealed the effects of incretin analog therapy and therapy withdrawal on adipose tissue physiology. By showing that incretin analog treatment followed by a dietary intervention minimizes body weight regain and restores adipose function, our research may contribute to the development of long-term therapy guidelines of incretin analog therapy for patients with obesity.