Classification of Therapeutic and Experimental Drugs for Brown Adipose Tissue Activation: Potential Treatment Strategies for Diabetes and Obesity

Abstract

Objective: Increasing efforts are being made towards pharmacologic activation of brown adipose tissue (BAT) in animals and humans for potential use in the treatment of obesity and diabetes. We and others have reported a number of animal studies using either experimental or therapeutic drugs. There are now efforts to translate these findings to human studies. The goal of this review is to evaluate the various drugs currently being used that have the potential for BAT activation.

Methods: Drugs were classified into 4 classes based on their mechanism of action. Class 1 drugs include the use of β3 adrenoceptor agonists for BAT activation. Class 2 drugs include drugs that affect norepinephrine levels and activate BAT with the potential of reducing obesity. Class 3 includes activators of peroxisome proliferator-activated receptor-γ in pursuit of lowering blood sugar, weight loss and diabetes and finally Class 4 includes natural products and other emerging drugs with limited information on BAT activation and their effects on diabetes and weight loss.

Results: Class 1 drugs are high BAT activators followed by Class 2 and 3. Some of these drugs have now been extended to diabetes and obesity animal models and human BAT studies. Drugs in Class 3 are used clinically for Type 2 diabetes, but the extent of BAT involvement is unclear.

Conclusion: Further studies on the efficacy of these drugs in diabetes and measuring their effects on BAT activation using noninvasive imaging will help in establishing a clinical role of BAT.

Fig. (1)

Schematic of Sites of Drug Action: Class 1 drugs act on the adipocyte cell membrane bound β3 adrenergic receptor (β3AR) triggering a cascade of events via cAMP. Class 2 drugs act on the norepinephrine transporter (NET) on the sympatheic nerve terminal and increase norepinephrine (NE) levels which then stimulates β3AR. Class 3 drugs activate peroxisome proliferator-activated receptor gamma (PPARγ). Class 4 drugs act on various pathways within the adipocyte. Abbreviations: AC: adenylate cyclase; Gs: stimulatory G-protein; ATP: adenosine triphosphate; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; TG: triglycerides; FFA: free fatty acids; UCP-1: uncoupling protein-1(found in mitochondria); Glu: glucose. Norepinephrine.

Fig. (2)

PET Images from Class 1 Drug Effects on Rat BAT: CL316,243 induced activation of BAT is seen in the PET image (B) and regional localization confirmed by PET/CT (A). Interscapular, periaortic, cervical and intercostal BAT regions are evident. The bilateral structure of activated interscapular BAT (IBAT) is evident in the ventral (C), dorsal (D) and caudal (E) views of IBAT (Figure adapted from Mirbolooki et al., 2011) [29].

Fig. (3)

Class 1 Drug Effects on Obesity and Type1 Diabetes Model: Graph showing effects of CL316,243 (CL) in the two rodent models. In Zucker rat obese models (and T2DM), uptake of ¹⁸F-FDG in Zucker lean (ZL) increased by +231% with CL316,243 while Zucker fat (ZF) were reduced by -44% with little effect of CL316,243. In T1DM streptozotocin (STZ) model, uptake of ¹⁸F-FDG in Sprague-Dawley normal (SD Nor) increased by +624% with CL316,243, whereas SD STZ was reduced by -70%. An increased uptake of ¹⁸F-FDG was seen SD STZ upon CL316,243 treatment, suggesting some recovery of BAT function.