Relation of adipose tissue to metabolic flexibility

Abstract

Metabolic flexibility is the capacity for skeletal muscle to shift reliance between lipids and glucose during fasting or in response to insulin. We hypothesized that body fat, adipose tissue characteristics, e.g. larger adipocytes, presence of inflammatory gene markers and impaired suppression of non-esterified fatty acids (NEFAs) during insulin infusion might be related to metabolic flexibility. We measured changes in respiratory quotient (DeltaRQ) before and during euglycemic-hyperinsulinemic clamp in healthy young males. Body fat by DXA, laboratory measurements, abdominal subcutaneous adipose tissue biopsies and fat cell size (FCS) were obtained after an overnight fast. Gene expression for 17 adipose tissue genes related to lipid synthesis, uptake, oxidation and storage, lipolysis and inflammation were measured. Reduced metabolic flexibility was associated with higher body fat, larger FCS and impaired insulin suppression of NEFAs. Metabolic flexibility was associated with higher serum adiponectin levels. Lower adipose tissue gene expression for inflammation markers was associated with greater NEFA suppression by insulin and metabolic flexibility. Combined, these results indicate that body fat, larger adipocytes, failure of insulin to suppress NEFAs, decreased adiponectin levels and inflammation markers in adipose tissue are associated with decreased insulin-stimulated glucose uptake and oxidation, which is an important component of reduced metabolic flexibility.

Conflict of interest statement

Conflict of interest

None.

Figures

Fig. 1

Body fatness, NEFAs after insulin infusion and adiponectin are related to reduced metabolic flexibility (ΔRQ) in healthy young men. Change in respiratory quotient (ΔRQ; metabolic flexibility) was measured before and during a euglycemic-hyperinsulinemic clamp (EHC) in the population of 56 healthy young men. ΔRQ was subdivided into quartiles and ANOVA was used to test for differences in biopsy and blood parameters across quartiles of metabolic flexibility (ΔRQ), with post hoc testing by mean equality contrast between different groups using the Tukey-Kramer HSD; alpha = 0.05. Type I error rate was set a priori at p < 0.05. Data are shown as means ± S.E. Levels which do not share the same letter are significantly different. (A) Percent body fat, (B) fat cell size, (C) serum adiponectin, (D) fasting non-esterified free fatty acids (NEFAs) as measured by enzyme assay and (E) insulin-suppressed NEFAs during insulin infusion of the EHC as measured by high-performance liquid chromatography (HPLC).

Fig. 2

Relationships between reduced metabolic flexibility (ΔRQ) and expressions of chemokines and macrophage markers. Change in respiratory quotient (ΔRQ; metabolic flexibility) was measured before and during a euglycemic-hyperinsulinemic clamp (EHC) in the population of 56 healthy young men. ΔRQ was subdivided into quartiles and was associated with gene expressions of chemokines and macrophage markers, with post hoc testing by mean equality contrast between different groups using the Tukey-Kramer HSD; alpha = 0.05. Type I error rate was set a priori at p < 0.05. mRNA expression data were normalized to 18S. Data are shown as means ± S.E. Levels which do not share the same letter are significantly different. (A) MCP-1 expression, (B) MIP-1α expression, (C) CD68 expression and (D) MAC-2 expression.

Fig. 3

Oxidative and non-oxidative carbohydrate (CHO) disposal are related to reduced metabolic flexibility (ΔRQ) in healthy young men. Higher fasting carbohydrate (CHO) oxidation (A) was associated with lower ΔRQ. Lower levels of insulin-suppressed CHO oxidation (B) and storage (C) were associated with lower ΔRQ. Delta RQ (ΔRQ) was subdivided into quartiles. ANOVA was used to test for differences in biopsy and blood parameters across quartiles of metabolic flexibility (ΔRQ), with post hoc testing by mean equality contrast between different groups using the Tukey-Kramer HSD; alpha = 0.05. Type I error rate was set a priori at p < 0.05. Data are shown as means ± S.E. All levels not connected by same letter are significantly different.

Fig. 4

A model for the role of adipose tissue in metabolic flexibility. Energy excess leads to increased body fatness (%) and hypertrophic adipocytes. Hypertrophic adipocytes secrete chemokines and lead to macrophage infiltration. The macrophage-infiltrated hypertrophic adipocytes decrease insulin-stimulated suppression of lipolysis, as well as decrease adiponectin secretion. Elevated levels of NEFAs during insulin infusion, coupled with decreased serum adiponectin levels, lead to an inhibition of insulin-stimulated glucose uptake and oxidation in skeletal muscle and a decreased capacity for fat oxidation.