Norepinephrine binds to the beta three adrenergic receptors. It stimulates the expression of PGC1alpha which in turn acts in several ways: it increases UCP1 (heat production), AMPK stimulates PGC1alpha, which stimulates NRF1 and TFAM (mitochondrial biogenesis) and stimulates UCP1. Other mediators involved in BAT thermogenesis include SIRT1 (enhances beta-adrenergic signaling and increases the gene expression of UCP1 and BMP8, which stimulates AMPK and HSL), stimulating thermogenesis. Also, BMP7 (increases UCP1) and PRDM16 (active PGC1alpha) are potent inducers of brown adipocyte differentiation. BAT has three substrate options: a) glucose: GLUT4 and TC10 bring glucose to the mitochondrial Krebs cycle, b) AKT phosphorylation facilitates GLUT4, c) free fatty acids (FFA): LPL releases FFA to the cell through CD36, where AP2 carries it to the mitochondria through CPT1, d) FFA stored in the fat droplet is maintained by PLIN; ATGL and HSL release FFA and CPT1 move to the mitochondria producing heat.

We studied the effect of metformin on the brown adipose tissue (BAT) in a fructose-rich-fed model, focusing on BAT proliferation, differentiation, and thermogenic markers.

C57Bl/6 mice received isoenergetic diets for ten weeks: control (C) or high-fructose (F). For additional eight weeks, animals received metformin hydrochloride (M, 250 mg/kg/day) or saline. After sacrifice, BAT and white fat pads were prepared for light microscopy and molecular analyses.

Body mass gain, white fat pads, and adiposity index were not different among the groups. There was a reduction in energy intake in the F group and energy expenditure in the F and FM groups. Metformin led to a more massive BAT in both groups CM and FM, associated with a higher adipocyte proliferation (β1-adrenergic receptor, proliferating cell nuclear antigen, and vascular endothelial growth factor), and differentiation (PR domain containing 16, bone morphogenetic protein 7), in part by activating 5′ adenosine monophosphate-activated protein kinase. Metformin also enhanced thermogenic markers in the BAT (uncoupling protein type 1, peroxisome proliferator-activated receptor gamma coactivator-1 alpha) through adrenergic stimuli and fibroblast growth factor 21. Metformin might improve mitochondrial biogenesis in the BAT (nuclear respiratory factor 1, mitochondrial transcription factor A), lipolysis (perilipin, adipose triglyceride lipase, hormone-sensitive lipase), and fatty acid uptake (lipoprotein lipase, cluster of differentiation 36, adipocyte protein 2).

Metformin effects are not linked to body mass changes, but affect BAT thermogenesis, mitochondrial biogenesis, and fatty acid uptake. Therefore, BAT may be a metformin adjuvant target for the treatment of metabolic disorders.