Metformin has been used clinically since 1957 for its efficacy and safety as therapy for type 2 diabetes. Besides ameliorating hyperglycemia without risk of hypoglycemia, metformin also lowers plasma triglyceride levels. Furthermore, a wealth of data shows that metformin facilitates weight loss in mice as well as humans. Due to its numerous metabolic benefits, researchers and clinicians are interested in the possibility of using metformin as treatment to combat obesity and other metabolic disorders such as non-alcoholic fatty liver disease (NAFLD). Despite being the most commonly prescribed anti-diabetic, metformin’s complete mechanism(s) for weight loss or for lowering glucose and lipids remains an enigma. Our studies show that metformin-treated mice exhibited decreased caloric intake, providing a viable mechanism for metformin to bring about weight loss. Intriguingly, we found that metformin induces PRDM16 to promote browning of iWAT and increase expression of thermogenic genes such as UCP1 and DIO2. However, metformin did not appear to increase energy expenditure. It’s possible that metformin’s effect on energy expenditure was masked since energy expenditure measurements were taken when metformin-treated mice were still losing weight and were in a state of negative energy balance. Recently, there has been much attention given to AMPK activators as exercise mimetics. Metformin is known to activate AMPK and similarly brings about many beneficial effects as exercise such as alleviation of obesity-induced NAFLD. SIRT1 stimulation by resveratrol and delivery of exogenous FGF21 mimics metformin’s ability to combat obesity and improve NAFLD. Collectively, these results implicate metformin, resveratrol, and exogenous administration of FGF21 as beneficial therapies for weight loss and amelioration of NAFLD.