Dataset Information

Obeticholic acid improves adipose morphometry and inflammation and reduces steatosis in dietary but not metabolic obesity in mice.

ABSTRACT:

Objective

Nonalcoholic steatohepatitis (NASH) is the outcome of interactions between overnutrition, energy metabolism, and adipose function. Obeticholic acid (OCA) improves steatosis in patients but for unknown reasons does not resolve NASH pathology. This study therefore investigated OCA effects in Wt mice, which develop obesity with atherogenic dietary feeding, and appetite-dysregulated, Alms1 mutant foz/foz mice fed the same diet, which develop metabolic obesity and diabetes.

Methods

OCA (1 mg/kg) was administered orally to female foz/foz mice and Wt littermates from weaning until 28 weeks. Adipose indices, glucose tolerance, and fatty liver pathology were studied. Experiments were repeated with OCA 10 mg/kg.

Results

OCA reduced body weight and hepatic lipids and improved glucose disposal only in Wt mice. OCA limited Wt adipose expansion, altered morphometry in favor of small adipocytes, enhanced expression of genes indicating adipose browning, and reduced crown-like structure number in visceral adipose tissue. foz/foz mice showed more crown-like structures in all compartments; OCA failed to alter adipose morphometry, browning, inflammation, or improve NASH severity, even at 10 mg/kg.

Conclusions

OCA improved adipose indices, glucose tolerance, and steatosis in a milder metabolic phenotype but failed to improve these factors in morbidly obese diabetic mice. These results help explain OCA's limited efficacy to reverse human NASH.

SUBMITTER: Haczeyni F

PROVIDER: S-EPMC5849463 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Obeticholic acid improves adipose morphometry and inflammation and reduces steatosis in dietary but not metabolic obesity in mice.

Haczeyni Fahrettin F Poekes Laurence L Wang Hans H Mridha Auvro R AR Barn Vanessa V Geoffrey Haigh W W Ioannou George N GN Yeh Matthew M MM Leclercq Isabelle A IA Teoh Narcissus C NC Farrell Geoffrey C GC

Obesity (Silver Spring, Md.) 20161102 1

<h4>Objective</h4>Nonalcoholic steatohepatitis (NASH) is the outcome of interactions between overnutrition, energy metabolism, and adipose function. Obeticholic acid (OCA) improves steatosis in patients but for unknown reasons does not resolve NASH pathology. This study therefore investigated OCA effects in Wt mice, which develop obesity with atherogenic dietary feeding, and appetite-dysregulated, Alms1 mutant foz/foz mice fed the same diet, which develop metabolic obesity and diabetes.<h4>Metho ...[more]

PMID: 27804232

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Project description:Equine metabolic syndrome (EMS) is a steadily growing endocrine disorder representing a real challenge in veterinary practice. As a multifactorial condition, EMS is characterized by three main metabolic abnormalities including insulin resistance, increased adiposity or obesity and hoof laminitis. Adipose tissue dysfunction is recognized as a core pathophysiological determinant of EMS, as it strongly participates to lipotoxicity and systemic metaflammation, both of which have been closely linked to the development of generalized insulin resistance. Besides, sex hormone binding globulin (SHBG) is an important sex steroids transporters that has been recently proposed as an important metabolic mediator. Therefore, the aim of this study was to verify whether SHBG treatment may ameliorate subcutaneous adipose tissue metabolic failure under EMS condition in terms of lipidome homeostasis, lipid metabolism programs, insulin signalling and local inflammation. Subcutaneous adipose tissue (SAT) biopsies were collected post-mortem from healthy (n = 3) and EMS (n = 3) slaughtered horses. SHBG protein has been applied to SAT samples from EMS horses for 24 h at a final concentration of 50 nM, while control groups (healthy and untreated EMS) were cultured in the presence of SHBG-vehicle only. Tissues from all groups were afterwards secured for downstream analysis of gene expression using RT-qPCR, protein levels by Western blot and ELISA assay and lipidomics through GC-MS technique. Obtained results showcased that SHBG intervention efficiently normalized the altered fatty acids (FAs) profiles by lowering the accumulation of saturated and trans FAs, as well as the pro-inflammatory arachidonic and linoleic acids. Moreover, SHBG showed promising value for the regulation of adipocyte lipolysis and engorgement by lowering the levels of perilipin-1. SHBG exerted moderated effect toward SCD1 and FASN enzymes expression, but increased the LPL abundance. Interestingly, SHBG exhibited a negative regulatory effect on pro-adipogenic stimulators and induced higher expression of KLF3, IRF3 and β-catenin, known as strong adipogenesis repressors. Finally, SHBG protein showed remarkable ability in restoring the insulin signal transduction, IR/IRS/Pi3K/AKT phosphorylation events and GLUT4 transporter abundance, and further attenuate pro-inflammatory response by lowering IL-6 tissue levels and targeting the PDIA3/ERK axis. Overall, the obtained data clearly demonstrate the benefice of SHBG treatment in the regulation of adipose tissue metabolism in the course of EMS and provide new insights for the development of molecular therapies with potential translational application to human metabolic disorders.

Project description:BackgroundNowadays, the number of obese people in the world has reached alarming proportions. During the expansion of adipose tissue, a number of functions such as activation and release of cytokines and hormones may be affected. This leads the body to a pro-inflammatory pattern, which may affect the proper functioning of many tissues. Thus, studying the mechanisms by which obesity induces physiological disorders is necessary, and may be facilitated by the use of animal models, in particular rodents. We sought to characterize the metabolic and adipose tissue changes resulting from a diet rich in fats and simple sugars in gerbils.MethodsWe divided 14 gerbils into two experimental groups that received a diet rich in simple carbohydrates and fats with 5,86 kcal/g (OB, n = 7) or a standard diet with 4.15 kcal/g (CT; n = 7) for 11 weeks. The animals had free access to water and food. The animal weight and food consumption were measured weekly. Blood, adipose tissue and liver of each animal were collected at the end of experiment. The following parameters were determined: cholesterol (COL), triglycerides (TGL) and glycemia (GLI) in the plasma; cytokines (IL-6, IL-10 and TNF-α) and hormones (adiponectin and leptin) in adipose tissue; activity of superoxide dismutase (SOD) and catalase (CAT), extraction and differentiation of fat and histology in liver.ResultsThe consumption of a diet rich in simple carbohydrates and fats led to increased total body weight and increased relative weights of liver and adipose tissue. In addition, we observed increased fasting glucose levels and circulating triglycerides, along with high TNF-α production in adipose tissue and increased total fat, cholesterol and triglyceride contents in the liver, contributing to higher intensity of hepatic steatosis. On the other hand, the animals of this group showed depletion in the enzyme activity of SOD and CAT in the liver, as well as reduction of IL-10 and adiponectin levels in adipose tissue.DiscussionHigh intake of saturated fat and simple carbohydrates establish the gerbil as an experimental model for the study of metabolic and hepatic abnormalities resulting from obesity.

Dataset Information

Obeticholic acid improves adipose morphometry and inflammation and reduces steatosis in dietary but not metabolic obesity in mice.

Objective

Methods

Results

Conclusions

Publications

Obeticholic acid improves adipose morphometry and inflammation and reduces steatosis in dietary but not metabolic obesity in mice.

Similar Datasets

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