Location: Obesity and Metabolism ResearchTitle: Diet induced-obesity and weight loss alter bile acid profiles and gene expression in insulin target tissues
|Lafrano, Michael - University Of California|
|Hernandez-carretero, Angelina - University Of California|
|Weber, Natalie - University Of California|
|Borkowski, Kamil - University Of California, Davis|
|Pedersen, Theresa - University Of California|
|Osborn, Olivia - University Of California|
Submitted to: Nutrition Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/20/2018
Publication Date: 7/24/2018
Citation: Lafrano, M.R., Hernandez-Carretero, A., Weber, N., Borkowski, K., Pedersen, T.L., Newman, J.W., Osborn, O. 2018. Diet induced-obesity and weight loss alter bile acid profiles and gene expression in insulin target tissues. Nutrition Research. 46:11-21. https://doi.org/10.1016/j.nutres.2017.07.006.
Interpretive Summary: Bile acids influence important bodily functions, including cholesterol breakdown, lipid synthesis, nutrient absorption, lipid/glucose control, and liver and intestinal health. In obesity, changes in bile acid signaling contribute to insulin resistance and affect circulating levels of cholesterol and triglycerides. Little research has been done on the effect of substantial weight loss after weight gain on bile acid metabolism. We investigated the impact of diet-dependent weight gain and loss on bile acid concentrations and related gene expression in tissues associated with the control and function of bile acids. To accomplish this goal, three groups of male mice (n=6/group) ate either: 1) a high fat diet for 18wk to induce obesity; 2) a low fat diet for 18wk to remain lean; 3) or a high fat diet for 9wk to induce obesity followed by the low fat diet for 9wk to induce weight loss. Liver, adipose, muscle, hypothalamus, and plasma samples were analyzed for bile acid concentrations and expression of genes associated with bile acid metabolism and function. The high fat diet caused obesity and insulin resistance within 9 weeks, and 9 weeks of low fat diet feeding returned these measures to the low fat diet group levels. Obesity decreased total liver bile acid concentrations (P=0.004), which returned to pre-obese levels with weight loss. The high fat diet generally increased bile acid concentrations in all other measured tissues, though the increase was not always statistically significant. Weight loss returned bile acids to pre-obese levels in plasma, but not adipose, muscle or hypothalamus. Also, numerous associations between bile acids within tissues remained after weight loss, as did expression changes in bile acid receptor, synthesis and transport genes. Therefore, weight gain and loss due to diet impact bile acid profiles and associated gene expression differently for each body tissue. As not all obesity-associated changes in bile acids were reversed by weight loss, bile acids may exert effects on the body after weight loss.
Technical Abstract: BACKGROUND: Bile acids (BAs) regulate systemic energy expenditure and metabolism and are influenced by weight gain and diet. However, the persistence of these changes with weight loss and diet change are unknown. OBJECTIVE: Investigate the impact of weight gain and loss due to diet change on BA concentrations and related gene expression in tissues associated with energy homeostasis. METHODS: Male C57BL6/6J mice (n=6/group) consumed: 1) 18wk of high fat and cholesterol diet (HFD); 2) 18wk of low fat and cholesterol diet (LFD); 3) 9wk of HFD with switch to LFD diet for 9wk (SWD). Liver, adipose, muscle, hypothalamus, and plasma samples were collected. Bile acids were measured by UPLC-MS/MS in all tissues. Gene expression was determined by qPCR in liver, adipose, and hypothalamus. RESULTS: The HFD induced obesity and insulin resistance within 9wk, and 9wk of LFD feeding returned these parameters to the LFD group levels. Obesity decreased total hepatic BA concentrations (P=0.004), which rebounded to pre-obese levels with weight loss. The HFD increased BA concentrations in all other measured tissues, although this was not always statistically significant due to high variance. Weight loss returned BAs to pre obese levels in plasma but not adipose, muscle or hypothalamus. Moreover, numerous HFD-induced correlations between BAs within tissues remained after weight loss, as did expression changes in bile acid receptor, synthesis and transport genes. CONCLUSION: Diet-induced weight gain and loss impact BA profiles and associated gene expression in a tissue specific manner. As not all obesity-associated changes in BAs are reversed by weight loss, these metabolites may transduce persistent effects in peripheral tissues.