Failure of dietary quercetin to alter the temporal progression of insulin resistance among tissues of C57BL/6J mice during the development of diet-induced obesity

• Published in: Diabetologia Vol. 52; no. 3; pp. 514 - 523
• Main Authors: Stewart, L. K, Wang, Z, Ribnicky, D, Soileau, J. L, Cefalu, W. T, Gettys, T. W
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.03.2009; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Adipocytes - physiology; adipose tissue; Animals; Biological and medical sciences; Biomedical research; Botanicals; Diabetes; Diabetes. Impaired glucose tolerance; Diet; Dietary Fats - adverse effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Energy; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Euglycaemic-hyperinsulinaemic clamp; Feeding Behavior; Glucose; Glucose Clamp Technique; Glucose Intolerance - etiology; Glucose Intolerance - physiopathology; Glucose uptake; Hepatic glucose production; Human Physiology; Hyperinsulinism; Insulin - physiology; Insulin resistance; Insulin Resistance - physiology; Internal Medicine; Kinases; Laboratory animals; Lipids; Liver; Liver - metabolism; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolic syndrome; Mice; Mice, Inbred C57BL; Muscle, Skeletal - metabolism; Obesity; Obesity - complications; Obesity - etiology; Obesity - physiopathology; Quercetin - therapeutic use; Signal Transduction; Treatment Failure; Triglycerides - metabolism; Baton Rouge Louisiana; United States > US; Botanicals; Insulin resistance; Glucose uptake; Adipose tissue; Hepatic glucose production; Euglycaemic–hyperinsulinaemic clamp; Endocrinopathy; Obesity; Diabetes mellitus; Rodentia; Nutrition disorder; Euglycaemic- hyperinsulinaemic clamp, Glucose uptake; Metabolic diseases; Glucose; Uptake; Feeding; Target tissue resistance; Vertebrata; Mammalia; Diet; Mouse; Animal; Development; Nutritional status
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-008-1252-0

Aims/hypotheses High-fat diets produce obesity and glucose intolerance by promoting the development of insulin resistance in peripheral tissues and liver. The present studies sought to identify the initial site(s) where insulin resistance develops using a moderately high-fat diet and to assess whether the bioflavonoid, quercetin, ameliorates progression of this sequence. Methods Four cohorts of male C57BL/6J mice were placed on diets formulated to be low-fat (10% of energy from fat), high-fat (45% of energy from fat) or high-fat plus 1.2% quercetin (wt/wt). After 3 and 8 weeks, cohorts were evaluated using euglycaemic-hyperinsulinaemic clamps, metabolomic analysis of fatty acylcarnitines and acute in vitro assessments of insulin signalling among tissues. Results After 3 and 8 weeks, the high-fat diet produced whole-body insulin resistance without altering insulin-dependent glucose uptake in peripheral tissues. The primary defect was impaired suppression of hepatic glucose production by insulin at both times. Quercetin initially exacerbated the effect of high-fat diet by further increasing hepatic insulin resistance, but by 8 weeks insulin resistance and hepatic responsiveness to insulin were similarly compromised in both high-fat groups. The high-fat diet, irrespective of quercetin, increased short-chain fatty acylcarnitines in liver but not in muscle, while reciprocally reducing hepatic long-chain fatty acylcarnitines and increasing them in muscle. Conclusions/interpretation Failure of insulin to suppress hepatic glucose output is the initial defect that accounts for the insulin resistance that develops after short-term consumption of a high-fat (45% of energy) diet. Hepatic insulin resistance is associated with accumulation of short- and medium-, but not long-chain fatty acylcarnitines. Dietary quercetin does not ameliorate the progression of this sequence.