A. BACKGROUND AND RATIONALE~Glucagon like peptide (GLP-1) agonists, such as liraglutide, exenatide, and semaglutide, have been increasingly used as a medication to address the current twin epidemics of diabetes and obesity. Their activities include increasing insulin production by pancreatic beta cells, improving insulin sensitivity in muscles and weight loss1,2. The mechanisms underpinning the weight loss caused by GLP-1 agonists have not yet been fully elucidated, but brown adipose tissue (BAT) appears to play an important role1,2.~BAT is a type of adipose tissue which predominates in infants to allow thermoregulation through adaptive thermogenesis, but it is also present in adults3. BAT activity also increases insulin sensitivity and whole body energy expenditure, and thus has the potential to treat type 2 diabetes and obesity4,5. Bilateral supraclavicular and axillary BAT account for approximately two thirds of total body BAT content 6. Although the precise role of BAT in human metabolism and energy balance is unknown, a clear link exists between obesity and BAT dysfunction in humans 4,5.~The effects of GLP-1 on BAT appears to be important in animal models. There is evidence that GLP-1 receptors (GLP-1R) are present in various hypothalamic nuclei (including the ventromedial nucleus and the dorsomedial nucleus) and their activation results in subsequent sympathetic outflow to BAT depots7,8, which in turn increases expression of genes in BAT required for thermogenesis including PGC1a and UCP-19. Additionally, GLP-1 appears to stimulate BAT also locally through GLP-1R expressed in brown adipocytes, increasing their intracellular thyroid activation10.~Given the interaction between GLP-1 and BAT, it has been hypothesized that the prominent weight loss activity of GLP-1 agonists in humans is the result of BAT activation. However, studies with various GLP-1 agonists have been equivocal. Utilizing liraglutide, some studies in diabetic patients have noted no increase in basal metabolic rate (BMR)12,13 while Horowitz et al. noted an increase in BMR 14 and no change in BAT activity was noted by Van Eyk et al.13. Utilizing exenatide, studies have not shown an increase in BMR 15,16, Janssen et al. observed an increase in BAT activity evaluated by PET16.~With more powerful GLP-1 agonists such as semaglutide entering in clinical practice, a better understanding of the relationship between GLP-1 and BAT is important. If BAT activity is found to be clinically significant as a mechanism of action of GLP-1 agonists, then the addition of adjuvants which enhance BAT activity could optimize the benefit of these medications.~Currently, the main methods available to assess BAT activity are PET-CT with 18F-fluorodeoxyglucose, single-photon-emission CT scanning with tracers such as 123 I-meta-iodobenzylguanidine or 99mTc-tetrofosmin, and/or tissue biopsy 17-19.These techniques have distinct disadvantages as they are expensive and require either the administration of radiopharmaceuticals or tissue sampling. Their utility is, therefore, greatly limited as they can only be conducted on a very small number of subjects and are unable to provide indices of BAT function in real-time. Symonds et al 20demonstrated the feasibility of using infrared thermography as a safe, reproducible, and robust technique for measuring the temperature of the skin overlying BAT depots in the supraclavicular region and quantifying BAT thermogenesis induced by a cold challenge.~We propose to assess BAT activity, using infrared thermography camera images, before individuals start weekly administration of semaglutide, at week 2- 4, and week 18-20. We hypothesize that this GLP-1 agonist, semaglutide, will cause an increase in BAT activity and a corresponsing increase in basal metabolic rate.~Utilizing a reproducible and non invasive measure of BAT activity, we hope to gain better understanding of BAT activity in concert with the metabolic status of patients commenced on semaglutide. This will not only allow insights into the mechanism of achieving weight loss with semaglutide, it will also allow better understanding of the importance of BAT activity manipulation in the therapy for obesity.
ABSTRACT Glucagon like peptide (GLP-1) agonists, such as liraglutide, exenatide, and semaglutide, have been increasingly used as a medication to address the current twin epidemics of diabetes and obesity. Their activities include increasing insulin production by pancreatic beta cells, improving insulin sensitivity in muscles and weight loss1,2. The mechanisms underpinning the weight loss caused by GLP-1 agonists have not yet been fully elucidated, but brown adipose tissue (BAT) appears to play an important role1,2.~We propose to assess BAT activity, using infrared thermography camera images, before individuals start weekly administration of semaglutide, at week 2-4, and week 18-20. We hypothesize that this GLP-1 agonist, semaglutide, will cause an increase in BAT activity and a corresponding increase in basal metabolic rate.