Cannabinoid Receptor Type 1 (CB1R) Signaling Regulates Hepatic Gluconeogenesis via Induction of Endoplasmic Reticulum-bound Transcription Factor cAMP-responsive Element-binding Protein H (CREBH) in Primary Hepatocytes
mice; obesity; Biochemistry & Molecular Biology; risk-factors; er stress; activation; food-intake; dysregulation; endocannabinoid system; overweight patients; rimonabant
Activated cannabinoid 1 receptor (CB1R) signaling has been implicated in the development of phenotypes associated with fatty liver, insulin resistance, and impaired suppression of hepatic glucose output. Endoplasmic reticulum stress-associated liver-specific transcription factor CREBH is emerging as a critical player in various hepatic metabolic pathways and regulates hepatic gluconeogenesis in diet-induced obese settings. In this study, we elucidated the critical role of CREBH in mediating CB1R signaling to regulate glucose homeostasis in primary rat and human hepatocytes. mRNA and protein levels and glucose production were analyzed in primary rat and human hepatocytes. ChIP assays were performed together with various transcriptional analyses using standard techniques. CB1R activation by 2-arachidonoylglycerol (2-AG) specifically induced CREBH gene expression via phosphorylation of the JNK signaling pathway and c-Jun binding to the AP-1 binding site in the CREBH gene promoter. 2-AG treatment significantly induced hepatic gluconeogenic gene expression and glucose production in primary hepatocytes, and we demonstrated that the CREBH binding site mutant significantly attenuated 2-AG-mediated activation of the gluconeogenic gene promoter. Endogenous knockdown of CREBH led to ablation of 2-AG-induced gluconeogenic gene expression and glucose production, and the CB1R antagonist AM251 or insulin exhibited repression of CREBH gene induction and subsequently inhibited gluconeogenesis in both rat and human primary hepatocytes. These results demonstrate a novel mechanism of action of activated CB1R signaling to induce hepatic gluconeogenesis via direct activation of CREBH, thereby contributing to a better understanding of the endocannabinoid signaling mechanism involved in regulating the hepatic glucose metabolism.
Chanda D; Kim D K; Li T G; Kim Y H; Koo S H; Lee C H; Chiang J Y L; Choi H S
Journal of Biological Chemistry
2011
2011-08
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1074/jbc.M111.224352" target="_blank" rel="noreferrer noopener">10.1074/jbc.M111.224352</a>
Obesity treatment: Broadening our perspective
body-mass index; Cardiovascular disease; dietary behaviors; dietary fiber; Environmental & Occupational Health; food-intake; glycemic index; low-fat; night-eating syndrome; obesity; patterns; Public; randomized controlled-trial; weight management; weight-loss
Objective: To selectively review the dietary literature to broaden perspectives on energy restriction as the primary determinant of successful obesity treatment. Methods: Forty-five articles describing novel dietary behaviors and nutrient intakes that may impact obesity treatment are examined. Results: Two areas of promising research were identified: (a) Dietary behaviors and patterns - eating frequency, meal timing, specific dietary pattern and (b) Nutritional factors - fat, fiber, glycemic load, carbohydrate. Conclusions: Caloric restriction leads to weight loss. However, promotion of dietary behaviors that focus primarily on cutting calories needs evaluation. There may be many dietary behaviors and patterns that promote weight loss and maintenance, making it essential to consider new nutritional approaches for obesity treatment.
Taylor E; Missik E; Hurley R; Hudak S; Logue E
American Journal of Health Behavior
2004
2004-05
Journal Article
<a href="http://doi.org/10.5993/ajhb.28.3.5" target="_blank" rel="noreferrer noopener">10.5993/ajhb.28.3.5</a>