The role of dietary fat in obesity-induced insulin resistance.
Consumption of excess calories results in obesity and insulin resistance and has been intensively studied in mice and humans. The objective of this study was to determine the specific contribution of dietary fat rather than total caloric intake to the development of obesity-associated insulin resistance. We used an intragastric feeding method to overfeed excess calories from a low-fat diet (and an isocalorically matched high-fat diet) through a surgically implanted gastric feeding tube to generate obesity in wild-type mice followed by hyperinsulinemic-euglycemic clamp studies to assess the development of insulin resistance. We show that overfeeding a low-fat diet results in levels of obesity similar to high-fat diet feeding in mice. However, despite a similar body weight, obese high-fat diet-fed mice are more insulin resistant than mice fed an isocaloric low-fat diet. Therefore, increased proportion of calories from dietary fat further potentiates insulin resistance in the obese state. Furthermore, crossover diet studies revealed that reduction in dietary fat composition improves glucose tolerance in obesity. In the context of the current obesity and diabetes epidemic, it is particularly important to fully understand the role of dietary macronutrients in the potentiation and amelioration of disease.
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California.
Denise E
DE
Lackey
Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; and.
Raul G
RG
Lazaro
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California.
Pingping
P
Li
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California.
Andrew
A
Johnson
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California.
Angelina
A
Hernandez-Carretero
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California.
Natalie
N
Weber
Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; and.
Ivetta
I
Vorobyova
Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; and.|Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California.
Hidekazu
H
Tsukomoto
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California; oosborn@ucsd.edu.
Olivia
O
Osborn
D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001835:Body Weight; D018932:Chemokine CCL2 / Q000378:metabolism; D018592:Cross-Over Studies; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D004041:Dietary Fats; D002149:Energy Intake; D004750:Enteral Nutrition; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D052243:Resistin / Q000378:metabolism; D058258:Serpin E2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D015850:Interleukin-6; D020738:Leptin; D052243:Resistin; C499623:Retn protein, mouse; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse
diabetes; high-fat diet; insulin resistance; insulin sensitivity; obesity