Metabolic endotoxemia and saturated fat contribute to circulating NGAL concentrations in subjects with insulin resistance.
OBJECTIVE
Lipocalin-2 (neutrophil gelatinase-associated lipocalin, NGAL) is an innate immune system protein that has been linked to insulin resistance and obesity, but the mechanisms behind these associations are poorly known. We hypothesized that endotoxin (lipopolysaccharide, LPS) and fat intake were in the background of these associations.


METHODS
We studied four cohorts: (1) a cross-sectional study in 194 subjects; (2) the changes in NGAL concentration induced by diet and weight loss in 36 obese women (with circadian rhythm in 8 of them); (3) the effects of acute fat intake on circulating NGAL concentration in 42 morbidly obese subjects; and (4) LPS-induced NGAL secretion ex vivo (whole blood and adipose tissue explants).


RESULTS
Serum NGAL concentration was significantly associated with fasting triglycerides and LPS-binding protein in patients with type 2 diabetes. In obese subjects, the intake of saturated fatty acids was the factor that best explained the variance of NGAL changes after weight loss (contributing independently to 14% of NGAL variance). In fact, weight loss significantly changed the circadian rhythm of NGAL. The acute increase in circulating NGAL after fat overload was significantly associated with fasting insulin (r=0.52, P<0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (r=0.36, P=0.02) and post-load triglyceride concentrations (r=0.38, P=0.018). LPS-induced NGAL secretion from adipose tissue explants did not change significantly, but LPS led to a significant increase in NGAL concentration in the whole blood obtained from patients with type 2 diabetes.


CONCLUSIONS
Metabolic endotoxemia and saturated fat might contribute to circulating NGAL concentration in patients with insulin resistance.
Moreno-Navarrete
J M
JM
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona (IdIBGi) and University Hospital Dr Josep Trueta, CIBER Fisiopatología de la Obesidad y Nutrición CB06/03/010, Girona, Catalonia, Spain.
Manco
M
M
Ibáñez
J
J
García-Fuentes
E
E
Ortega
F
F
Gorostiaga
E
E
Vendrell
J
J
Izquierdo
M
M
Martínez
C
C
Nolfe
G
G
Ricart
W
W
Mingrone
G
G
Tinahones
F
F
Fernández-Real
J M
JM
D000209:Acute-Phase Proteins / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D015992:Body Mass Index; D002352:Carrier Proteins / Q000097:blood; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000276:immunology; D004041:Dietary Fats / Q000008:administration & dosage*; D019446:Endotoxemia / Q000097:blood* / Q000276:immunology; D005215:Fasting / Q000097:blood; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000276:immunology; D007333:Insulin Resistance; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood; D008875:Middle Aged; D009767:Obesity, Morbid / Q000097:blood* / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D015431:Weight Loss / Q000502:physiology; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D004041:Dietary Fats; D000071068:Lipocalin-2; D054834:Lipocalins; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D014280:Triglycerides; D000099231:Lipopolysaccharide-Binding Protein; C489506:LCN2 protein, human