Effects of metformin on metabolism of white and brown adipose tissue in obese C57BL/6J mice

Abstract

BackgroundTo investigate effects of metformin on the regulation of proteins of white adipose tissue (WAT) and brown adipose tissue (BAT) in obesity and explore the underlying mechanisms on energy metabolism.MethodsC57BL/6J mice were fed with normal diet (ND, n = 6) or high-fat diet (HFD, n = 12) for 22 weeks. HFD-induced obese mice were treated with metformin (MET, n = 6). After treatment for 8 weeks, oral glucose tolerance test (OGTT) and hyperinsulinemic–euglycemic clamp were performed to evaluate the improvement of glucose tolerance and insulin sensitivity. Protein expressions of WAT and BAT in mice among ND, HFD, and MET group were identified and quantified with isobaric tag for relative and absolute quantification (iTRAQ) coupled with 2D LC–MS/MS. The results were analyzed by MASCOT, Scaffold and IPA.ResultsThe glucose infusion rate in MET group was increased significantly compared with HFD group. We identified 4388 and 3486 proteins in WAT and BAT, respectively. As compared MET to HFD, differential expressed proteins in WAT and BAT were mainly assigned to the pathways of EIF2 signaling and mitochondrial dysfunction, respectively. In the pathways, CPT1a in WAT, CPT1b and CPT2 in BAT were down-regulated by metformin significantly.ConclusionsMetformin improved the body weight and insulin sensitivity of obese mice. Meanwhile, metformin might ameliorate endoplasmic reticulum stress in WAT, and affect fatty acid metabolism in WAT and BAT. CPT1 might be a potential target of metformin in WAT and BAT.

Intestinal AMPK modulation of microbiota mediates crosstalk with brown fat to control thermogenesis

“…Recent reports indicate that changes in gut microbiota can modulate BAT thermogenesis and whole-body energy expenditure 19 – 21 . Intriguingly, as oral administration of AMPK activators metformin and berberine alters gut microbiota composition 22 , intestinal AMPK may mediate crosstalk with BAT through regulatory effects on gut microbiota profile.…”

Metformin reduces macrophage HIF1α-dependent proinflammatory signaling to restore brown adipocyte function in vitro

“…Regarding the impact of metformin in the interactome between macrophages and brown adipocytes in BAT functionality in obesity, we found an increase in Ppargc1a and Ucp1 mRNAs, as well as UCP1 protein expression upon cold exposure in mice treated with metformin for 6 weeks, an effect likely related to the inhibition of HIF1α. A recent study associated the effect of metformin in HFD-fed mice with lipid metabolism in BAT by reducing Cpt1b and Cpt2 expression [ 78 ]. These authors conclude that this reduction might attenuate diet-induced thermogenesis; although, this contrasts with the well-known relevance of fatty acid oxidation for BAT thermogenesis.…”

Polygonum multiflorum Thunb. Hot Water Extract Reverses High-Fat Diet-Induced Lipid Metabolism of White and Brown Adipose Tissues in Obese Mice

“…However, no significant changes were seen in the UCP1 and CPT2 gene expressions among the study groups. A recent study showed that an HFD stimulated FA β-oxidation by increasing CPT1B and CPT2 expressions, whereas metformin (a drug for the treatment of type 2 diabetes) significantly down-regulated the CPT1B and CPT2 expressions in BAT compared with HFD-fed mice, indicating that metformin might improve the energy metabolism of BAT and might reduce compensated energy expenditure [ 43 ]. As a result, the HFD-fed group exhibited blunt mitochondrial β-oxidation associated with a decrease in the ability to expend diet-derived energy as heat in response to a fat overload in BAT.…”