Anti-Obesity Effects of Metformin: A Scoping Review Evaluating the Feasibility of Brown Adipose Tissue as a Therapeutic Target

Abstract

Brown adipose tissue (BAT) is increasingly recognized as the major therapeutic target to promote energy expenditure and ameliorate diverse metabolic complications. There is a general interest in understanding the pleiotropic effects of metformin against metabolic complications. Major electronic databases and search engines such as PubMed/MEDLINE, Google Scholar, and the Cochrane library were used to retrieve and critically discuss evidence reporting on the impact of metformin on regulating BAT thermogenic activity to ameliorate complications linked with obesity. The summarized evidence suggests that metformin can reduce body weight, enhance insulin sensitivity, and improve glucose metabolism by promoting BAT thermogenic activity in preclinical models of obesity. Notably, this anti-diabetic agent can affect the expression of major thermogenic transcriptional factors such as uncoupling protein 1 (UCP1), nuclear respiratory factor 1 (NRF1), and peroxisome-proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) to improve BAT mitochondrial function and promote energy expenditure. Interestingly, vital molecular markers involved in glucose metabolism and energy regulation such as AMP-activated protein kinase (AMPK) and fibroblast growth factor 21 (FGF21) are similarly upregulated by metformin treatment in preclinical models of obesity. The current review also discusses the clinical relevance of BAT and thermogenesis as therapeutic targets. This review explored critical components including effective dosage and appropriate intervention period, consistent with the beneficial effects of metformin against obesity-associated complications.

Keywords: brown adipose tissue; metabolism; metformin; obesity; therapeutic target; thermogenesis.

Figure 1

Schematic representation of the study’s selection procedure. In summary, after removing duplicates, only 49 studies were screened; of these, 39 full-text articles were assessed for eligibility, and only 21 articles met the inclusion criteria and are critically discussed with the current review.

Figure 2

Illustration of the general mechanism of brown adipose tissue (BAT) activation and recruitment, as well as the other molecular mechanisms involved. Briefly, cold exposure, exercise, natural/pharmacological products, and other stimuli can activate sympathetic neurons innervating BAT release norepinephrine (NE), which binds to β3-adrenergic receptors (β3-AR) converting ATP to cyclic adenosine monophosphate (cAMP). Subsequently, cAMP activates protein kinase A (PKA), which then activate hormone-sensitive lipase (HSL) to liberate fatty acids (FAs) from triacylglyceride (TAG) stores through lipolysis, which in turn upregulate uncoupling protein 1 (UCP1) located in the mitochondria. Subsequently, the uptake of circulating free fatty acids (FFAs) and glucose contributes to the regeneration of intracellular triglyceride stores. Glucose is transported into the cell by glucose transporters (GLUTs), while FFAs are transported via cluster of differentiation 36 (CD36). On the other hand, activation of AM-activated protein kinase (AMPK) induces the complex of adipogenic and thermogenic transcriptional factors such as NAD-dependent deacetylase sirtuin-1 (SIRT1), proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), and transcriptional factor PR domain containing 16 (PRDM16), which in turn increase UCP-1-driven thermogenesis and energy expenditure.

Figure 3

An overview of the most prominent mechanisms of action and impact of metformin on different metabolic diseases in conditions of metabolic syndrome. AMPK: AMP-activated protein kinase, cAMP: cyclic adenosine monophosphate, FGF21: fibroblast growth factor 21, GLP-1R: glucagon-like peptide 1 receptor, LDL: low-density lipoprotein.

Figure 4

The main putative molecular mechanisms involved in the anti-obesity effects of metformin mediated by brown adipose tissue function. AMPK: AMP-activated protein kinase, FGF21: fibroblast growth factor 21, Nrf1: nuclear respiratory factor 1: PGC-1α, peroxisome-proliferator-activated receptor gamma coactivator 1-alpha, UCP1: uncoupling protein 1, mg: milligram, kg; kilogram, wks: weeks.