Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice

Abstract

Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.

Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH

“…In support of this, oral dosing of BAM15 (∼85 mg/kg/day) was independently shown to prevent diet-induced obesity and improve glycemic control through alterations in whole-body energy expenditure, reduced adiposity, and AMPK-mediated suppression of WAT lipogenesis [ 112 ], supporting a crucial role of adipose tissue in mediating BAM15's beneficial effects. Interestingly, previous studies did not demonstrate an adipose-targeted depot for BAM15-mediated uncoupling [ 111 ]; however, differences in dose routes and pharmacokinetic study designs could explain these discrepancies.…”

“…demonstrated that BAM15 is orally bioavailable and reduces body weight due to increases in whole-body energy expenditure and reductions in fat mass. BAM15 administration to Western diet-fed mice led to reductions in hypertriglyceridemia, hepatic steatosis, and hepatic inflammation as well as improvements in whole-body insulin sensitivity without altering body temperature or renal/hepatic toxicity [ 111 ]. While the exact mechanisms of BAM15's anti-obesity effects remain to be determined, the authors attributed these beneficial effects to BAM15-mediated uncoupling in hepatocytes and increases in hepatic substrate utilization.…”

“…Given BAM15's ability to increase mitochondrial respiration across multiple cell types, it is plausible that its uncoupling action in extrahepatic tissues may contribute to its anti-obesity effects. Indeed, hyperinsulinemic-euglycemic clamp studies demonstrated that BAM15 enhanced insulin sensitivity in skeletal muscle and white adipose tissue [ 111 ]. In support of this, oral dosing of BAM15 (∼85 mg/kg/day) was independently shown to prevent diet-induced obesity and improve glycemic control through alterations in whole-body energy expenditure, reduced adiposity, and AMPK-mediated suppression of WAT lipogenesis [ 112 ], supporting a crucial role of adipose tissue in mediating BAM15's beneficial effects.…”

Energy Metabolism and Aging

“…Research in this field is very active and several novel approaches to stimulating energy expenditure in order to improve metabolic health have been reported while this article was being finalized. Treating mice with an orally bioavailable mitochondrial uncoupler, BAM15, was shown to increase nutrient oxidation, and decrease adiposity without altering food intake, and improve insulin sensitivity [ 95 ]. These actions reversed diet-induced obesity and would be expected to promote healthy aging.…”

Delivery of MMP-12 siRNA with a Nanocarrier Improves the Homeostasis of the Small Intestine and Metabolic Dysfunction in High-Fat Diet Feeding-Induced Obese Mice

“…Over the last 40 years, the prevalence of obesity has almost tripled worldwide 3 . The development of obesity is closely associated with multiple diseases, such as type 2 diabetes, hepatic steatosis, cardiovascular diseases, and even cancer [4][5][6][7][8][9] . Hence, obesity is a great threat to public health and causes an economic burden for society.…”