title: Plasma sphingolipids are biomarkers of metabolic syndrome in non-human primates maintained on a Western-style diet.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Eli Lilly and Company, Indianapolis, IN 46285, USA. brozinick_joseph_t@lilly.com
authors.forename: J T
authors.initials: JT
authors.lastname: Brozinick
authors.forename: E
authors.initials: E
authors.lastname: Hawkins
authors.forename: H
authors.initials: H
authors.lastname: Hoang Bui
authors.forename: M-S
authors.initials: MS
authors.lastname: Kuo
authors.forename: B
authors.initials: B
authors.lastname: Tan
authors.forename: P
authors.initials: P
authors.lastname: Kievit
authors.forename: K
authors.initials: K
authors.lastname: Grove
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002518:Ceramides / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000209:etiology; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D005632:Fructose / Q000009:adverse effects; D007333:Insulin Resistance; D008253:Macaca mulatta; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood* / Q000209:etiology; D009765:Obesity / Q000097:blood* / Q000150:complications; D012307:Risk Factors; D051102:Serine C-Palmitoyltransferase / Q000097:blood*; D013107:Sphingolipids / Q000097:blood*; D014633:Valine / Q000097:blood
chemical_list: D015415:Biomarkers; D002518:Ceramides; D013107:Sphingolipids; D005632:Fructose; D051102:Serine C-Palmitoyltransferase; D014633:Valine