Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition?

Abstract

Objective: Lipotoxicity and ectopic fat deposition reduce insulin signaling. It is not clear whether excess fat deposition in nonadipose tissue arises from excessive fatty acid delivery from adipose tissue or from impaired adipose tissue storage of ingested fat.

Research design and methods: To investigate this we used a whole-body integrative physiological approach with multiple and simultaneous stable-isotope fatty acid tracers to assess delivery and transport of endogenous and exogenous fatty acid in adipose tissue over a diurnal cycle in lean (n = 9) and abdominally obese men (n = 10).

Results: Abdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period. However, adipose tissue fat storage after meals was substantially depressed in the obese men. This was especially so for chylomicron-derived fatty acids, representing the direct storage pathway for dietary fat. Adipose tissue from the obese men showed a transcriptional signature consistent with this impaired fat storage function.

Conclusions: Enlargement of adipose tissue mass leads to an appropriate downregulation of systemic NEFA delivery with maintained plasma NEFA concentrations. However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage. This adipose tissue response to obesity may provide the pathophysiological basis for ectopic fat deposition and lipotoxicity.

FIG. 1.

Arterial plasma concentrations of NEFA (A), TG (B), glucose (C), and insulin (D) in lean males (●) and abdominally obese males (○).

FIG. 2.

The rate of appearance (R_a) of NEFA in lean and abdominally obese men shown as total body R_a and adjusted for lean and fat mass, respectively. The R_a of NEFA: whole-body (A), expressed per lean mass (B), and per total fat mass (C) in lean (●) and abdominally obese men (○). Three meals were given as indicated by the dotted vertical lines. The R_a of NEFA (μmol/min) was significantly higher in the abdominally obese group compared with the lean group (A) (time × group, P = 0.009). When the data were calculated and expressed as rate of disappearance (Rd) of NEFA, i.e., normalized per lean body mass (μmol · min⁻¹ [lean mass (kg)]⁻¹), this difference disappeared (P = 0.14). The abdominally obese men had significantly lower R_a of NEFA when expressed per total fat mass (μmol · min⁻¹ [fat mass (kg)]⁻¹, P = 0.029).

FIG. 3.

Adipose tissue blood flow and abdominal adipose tissue NEFA release, TG extraction and glucose uptake. The abdominally obese men (○) had significantly lower adipose tissue blood flow (time × group, P = 0.001) compared with the lean men (●) (A). The release of NEFA and the extraction of TG from plasma (nmol · 100 g⁻¹ · min⁻¹) was significantly lower in the tissue of the abdominally obese men (○) compared with lean men (●) (B and C) (both time × group, P = 0.001). Glucose uptake by adipose tissue was lower (P < 0.001) in the adipose tissue in the abdominally obese men (○) than in lean men (●) (D). The extraction of ¹³C-TG from each meal (meal 1 indicated by ●, meal 2 by ○, and meal 3 by ▾) in lean men (E) and in abdominally obese men (F) shows a diminution (P < 0.01) of ¹³C-TG extraction in the abdominally obese men in line with the net TG extraction (C). AT, adipose tissue.

FIG. 4.

Total transcapillary flux of fatty acids across adipose tissue (A) in lean (●) and abdominally obese (○) men following ingestion of three meals (as indicated by the dotted vertical lines). B shows the transcapillary flux of [²H₂]-palmitate, which is dominated by the label carried in [²H₂]-TG (VLDL). C shows the percentage of meal fat content deposited in adipose tissue after three sequential meals (meal 1, meal 2, meal 3) in lean (■) and abdominally obese (□) males. This was calculated from the transcapillary flux (A) where each 5-h time period (AUC) multiplied for body fat mass to arrive at total body fat being stored. The denominator for each time period is the fat content in the meal. Lean men show a significant meal × fractional uptake effect (P = 0.009), whereas the effect is statistically nonsignificant in the abdominally obese men. AT, adipose tissue.