title: Cannabinoid receptor type 1 mediates high-fat diet-induced insulin resistance by increasing forkhead box O1 activity in a mouse model of obesity.
abstract: Hepatic glucose production is promoted by forkhead box O1 (FoxO1) under conditions of insulin resistance. The overactivity of cannabinoid receptor type 1 (CB1R) partly causes increased liver fat deposits and metabolic dysfunction in obese rodents by decreasing mitochondrial function. The aim of the present study was to investigate the role of FoxO1 in CB1R-mediated insulin resistance through the dysregulation of mitochondrial function in the livers of mice with high-fat diet (HFD)-induced obesity. For this purpose, male C57BL/6 mice were randomly assigned to groups and either fed a standard diet (STD), a HFD, or a HFD with 1-week treatment of the CB1R inverse agonist, AM251, at 1 or 5 mg/kg. For in vitro experiments, AML12 hepatocytes were incubated with FoxO1 siRNA prior to challenge with arachidonyl-2'-chloroethylamide (ACEA) or a high concentration of free fatty acids (HFFA). Plasma parameters were analyzed using colorimetric methods. Liver histopathology and hepatic status markers were examined. The HFD-fed mice exhibited an increase in CB1R levels in the liver. Moreover, in response to increased hepatic oxidative stress, the HFD-fed mice also displayed hepatic mitochondrial dysfunction, as indicated by the decreased mRNA levels of carnitine palmitoyltransferase-1 (CPT-1), mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF-1) and citrate synthase. On the contrary, these effects in the HFD-fed mice were reversed by treatment with 5 mg/kg AM251. The administration of AM251 suppressed the induction of FoxO1, phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) expression in the livers of the mice fed a HFD by enhancing the phosphorylation of insulin signaling cascades thus, further lowering the high level of the homeostatic model assessment of insulin resistance (HOMA‑IR) index. In our in vitro experiments, transfection with FoxO1 siRNA prevented the HFFA- and ACEA-induced decrease in the gene expression of mitochondrial biogenesis-related factors, and abrogated the HFFA- and ACEA-induced increase in PEPCK and G6Pase expression. Taken together, our findings suggest that the anti-insulin resistance effect of AM251, which leads to an improvement of mitochondrial function in hepatic steatosis, is mediated through FoxO1.
authors: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors: Chin-Chang
authors: CC
authors: Chen
authors: Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Tao-Yuan, Taiwan, R.O.C.
authors: Tzung-Yan
authors: TY
authors: Lee
authors: Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors: Ching-Fai
authors: CF
authors: Kwok
authors: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors: Yung-Pei
authors: YP
authors: Hsu
authors: Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors: Kuang-Chung
authors: KC
authors: Shih
authors: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors: Yan-Jie
authors: YJ
authors: Lin
authors: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors: Low-Tone
authors: LT
authors: Ho
mesh_terms: D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D006609:High Mobility Group Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051265:NF-E2-Related Factor 1 / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000378:metabolism*
chemical_list: D063386:Cannabinoid Receptor Agonists; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D006609:High Mobility Group Proteins; D051265:NF-E2-Related Factor 1; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; C081930:Tfam protein, mouse; C103505:AM 251; D002950:Citrate (si)-Synthase