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High-saturated-fat diet-induced obesity causes hepatic interleukin-6 resistance via endoplasmic reticulum stress. 2019

Logan K Townsend, and Kyle D Medak, and Willem T Peppler, and Grace M Meers, and R Scott Rector, and Paul J LeBlanc, and David C Wright
Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.

The relationship between liver interleukin-6 (IL-6) resistance following high-fat diet (HFD)-induced obesity and glucose intolerance is unclear. The purpose of this study was to assess the temporal development of hepatic IL-6 resistance and the role of endoplasmic reticulum (ER) stress in this process. We hypothesized that HFD would rapidly induce hepatic IL-6 resistance through a mechanism involving ER stress. Male C57BL/6N mice consumed chow or a HFD (60%) derived from lard (saturated) or olive oil (monounsaturated) for 4 days or 7 weeks before being injected intraperitoneally with IL-6 (6 ng·kg-1). Glucose, insulin, and pyruvate tolerance tests were used as proxies for systemic glucose metabolism and hepatic glucose production, respectively. Primary mouse hepatocytes were incubated with palmitate (saturated) and oleate (unsaturated) overnight, then treated with 20 ng/ml IL-6. ER stress was induced via tunicamycin or prevented by sodium phenylbutyrate (PBA). Seven weeks of a saturated, but not monounsaturated, HFD reduced hepatic IL-6 signaling in conjunction with hepatic ER stress. Palmitate directly impaired IL-6 signaling in hepatocytes along with inducing ER stress. Pharmacologically induced ER stress caused hepatic IL-6 resistance, whereas PBA reversed HFD-induced IL-6 resistance. Chronic HFD-induced obesity is associated with hepatic IL-6 resistance due to saturated FA-induced ER stress.

UI MeSH Term Description Entries
D007328 Insulin A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1). Iletin,Insulin A Chain,Insulin B Chain,Insulin, Regular,Novolin,Sodium Insulin,Soluble Insulin,Chain, Insulin B,Insulin, Sodium,Insulin, Soluble,Regular Insulin
D007333 Insulin Resistance Diminished effectiveness of INSULIN in lowering blood sugar levels: requiring the use of 200 units or more of insulin per day to prevent HYPERGLYCEMIA or KETOSIS. Insulin Sensitivity,Resistance, Insulin,Sensitivity, Insulin
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008297 Male Males
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D009765 Obesity A status with BODY WEIGHT that is grossly above the recommended standards, usually due to accumulation of excess FATS in the body. The standards may vary with age, sex, genetic or cultural background. In the BODY MASS INDEX, a BMI greater than 30.0 kg/m2 is considered obese, and a BMI greater than 40.0 kg/m2 is considered morbidly obese (MORBID OBESITY).
D010654 Phenylbutyrates Derivatives of 4-phenylbutyric acid, including its salts and esters.
D004041 Dietary Fats Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. Fats, Dietary,Dietary Fat,Fat, Dietary
D005947 Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Dextrose,Anhydrous Dextrose,D-Glucose,Glucose Monohydrate,Glucose, (DL)-Isomer,Glucose, (alpha-D)-Isomer,Glucose, (beta-D)-Isomer,D Glucose,Dextrose, Anhydrous,Monohydrate, Glucose
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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