Plasma sphingolipids are biomarkers of metabolic syndrome in non-human primates maintained on a Western-style diet

• Published in: International Journal of Obesity Vol. 37; no. 8; pp. 1064 - 1070
• Main Authors: BROZINICK, J. T, HAWKINS, E, HOANG BUI, H, KUO, M.-S, TAN, B, KIEVIT, P, GROVE, K
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.08.2013
• Subjects: Animals; Biological and medical sciences; Biological markers; Biomarkers; Biomarkers - blood; Carbohydrates; Ceramides - blood; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - etiology; Diagnosis; Diet; Diet, High-Fat - adverse effects; Disease Models, Animal; Disease Progression; Enzymes; Fructose - adverse effects; Glucose; Insulin Resistance; Lipids; Macaca mulatta; Male; Measurement; Medical sciences; Metabolic diseases; Metabolic syndrome; Metabolic Syndrome - blood; Metabolic Syndrome - etiology; Metabolic syndrome X; Miscellaneous; Monkeys & apes; Obesity; Obesity - blood; Obesity - complications; Original; Other metabolic disorders; Physiological aspects; Plasma; Primates; Proteins; Risk Factors; Serine C-Palmitoyltransferase - blood; Sphingolipids; Sphingolipids - blood; Valine - blood; Oregon; United States > US; Indianapolis Indiana; Endocrinopathy; Pancreatic hormone; Monkey; Biological marker; Cardiovascular disease; Macaca mulatta; Metabolic syndrome; Blood plasma; Simioidea; Ceramide; Primates; Nutritional status; Obesity; Nutrition; Nutrition disorder; Sphingolipid; Metabolic diseases; Insulin; Feeding; rhesus monkey; Target tissue resistance; Vertebrata; Mammalia; Diet; Insulin resistance
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2012.191

The intake of a Western diet enriched in animal fat has been shown to be a major risk factor for Type 2 diabetes and obesity. Previous rodent studies have indicated that these conditions may be triggered by the accumulation of the sphingolipid ceramide in insulin-sensitive tissues. However, data are lacking in this regard from both humans and non-human primates. Here we have investigated the relationship between plasma ceramides and metabolic syndrome in Rhesus macaques fed a high-fat and high-fructose (HFFD) 'western' diet. We investigated this relationship in cohorts of monkeys fed a HFFD for a period of 8 months to 5 years. Animals were classified as control, pre-diabetic or diabetic based on fasting plasma parameters and insulin sensitivity. HFFD treatment produced significant increases in body weight and body fat and also resulted in a decline in insulin sensitivity. In parallel to the reduction in insulin sensitivity, significant increases in both plasma ceramide and dihydroceramide levels were observed, which further increased as animals progressed to the diabetic state. Plasma levels of the rare sphingolipid C18:0 deoxysphinganine, a marker of increased metabolic flux through serine palmitoyl transferase (SPT), were also elevated in both pre- and diabetic animals. Furthermore, plasma serine levels were significantly elevated in diabetic monkeys, which may indicate a shift in SPT substrate selectivity from serine to alanine or glycine. In contrast, branch chain amino acids were unchanged in pre-diabetic non-human primates, and only plasma valine levels were elevated in diabetic animals. Together, these data indicate that HFFD induces de novo synthesis of ceramides in non-human primates, and that increased production of plasma ceramides is significantly correlated with the decline in insulin sensitivity.