Introduction:
Obesity is a major global health problem, with over one third of adults in the US classified as obese. Obesity often leads to a state of insulin resistance (IR), type 2 diabetes (T2D) and its complications. We previously showed that the receptor for advanced glycation end products (RAGE) and its ligands contribute to the pathogenesis of obesity and IR, as whole body and adipocyte-specific
Ager
(gene encoding RAGE) deleted mice fed a high fat diet (HFD) were significantly protected from weight gain and IR. Here, we hypothesize that myeloid RAGE contributed to IR upon HFD feeding.
Methods:
We generated mice with myeloid-specific (MDR) LyzMCre(+/+).Ager
flox/flox
and adipocyte and myeloid-specific (Double Knockouts) AdipoQCre(-/+)LyzMCre(+/+).Ager
flox/flox
deletion of
Ager
and LysMCre mice were used as control. Mice were fed either standard chow (LFD) or HFD (60% kcal/fat) for 3 months starting at age 6 weeks. Mice were assessed for body mass and composition, glucose and insulin sensitivity and whole body glucose metabolism by hyperinsulinemic-euglycemic clamp studies.
Results:
After 3 months HFD, there were no significant differences in body mass, body composition, food intake, energy expenditure and physical activity of the MDR mice vs. controls. Similar findings were observed in mice fed LFD. However, surprisingly, in HFD-fed mice, insulin tolerance tests and hyperinsulinemic-euglycemic clamp studies showed decreased insulin sensitivity and insulin action in the MDR vs. control mice, indicating that the MDR mice were more insulin resistant. The Double Knockout (myeloid/adipocyte) Cre (+) mice were more glucose tolerant and insulin sensitive compared to MDR mice, showing that deletion of
Ager
in the adipocytes rescued the adverse effects of
Ager
deletion in myeloid cells.
Conclusions:
Myeloid
Ager
protects from IR in mice fed HFD. Furthermore, in MDR mice, concomitant adipocyte-specific deletion of
Ager
rescues these mice from IR and, at the same time, reduces HFD-induced adiposity. The mechanisms underlying these findings are under active investigation.
Clenbuterol-Induced Insulin Resistance in Calves Measured by Hyperinsulinemic, Euglycemic Clamp Technique
