Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity

Abstract

Visceral adipose tissue (VAT) is an important risk factor for obesity-related metabolic disorders. Therefore, a reduction in VAT has become a key goal in obesity management. However, VAT is correlated with intrahepatic triglyceride (IHTG) content, so it is possible that IHTG, not VAT, is a better marker of metabolic disease. We determined the independent association of IHTG and VAT to metabolic function, by evaluating groups of obese subjects, who differed in IHTG content (high or normal) but matched on VAT volume or differed in VAT volume (high or low) but matched on IHTG content. Stable isotope tracer techniques and the euglycemic-hyperinsulinemic clamp procedure were used to assess insulin sensitivity and very-low-density lipoprotein-triglyceride (VLDL-TG) secretion rate. Tissue biopsies were obtained to evaluate cellular factors involved in ectopic triglyceride accumulation. Hepatic, adipose tissue and muscle insulin sensitivity were 41, 13, and 36% lower (P < 0.01), whereas VLDL-triglyceride secretion rate was almost double (P < 0.001), in subjects with higher than normal IHTG content, matched on VAT. No differences in insulin sensitivity or VLDL-TG secretion were observed between subjects with different VAT volumes, matched on IHTG content. Adipose tissue CD36 expression was lower (P < 0.05), whereas skeletal muscle CD36 expression was higher (P < 0.05), in subjects with higher than normal IHTG. These data demonstrate that IHTG, not VAT, is a better marker of the metabolic derangements associated with obesity. Furthermore, alterations in tissue fatty acid transport could be involved in the pathogenesis of ectopic triglyceride accumulation by redirecting plasma fatty acid uptake from adipose tissue toward other tissues.

Fig. 1.

Hepatic (A), skeletal muscle (B), and adipose tissue (C) insulin sensitivity in subjects matched on visceral adipose tissue (VAT) volume with either normal or high intrahepatic triglyceride (IHTG) content and subjects matched on IHTG content who had either low or high VAT volume. AU, arbitrary units. Values are means ± SEM. *, value is significantly different from the corresponding value in the normal IHTG group, P < 0.05.

Fig. 2.

Very-low-density lipoprotein–triglyceride (VLDL-TG) secretion rate (A) and the relative contribution of systemic (generated primarily by lipolysis of s.c. adipose tissue triglycerides) and nonsystemic fatty acids (generated primarily by lipolysis of intrahepatic triglycerides) to VLDL-TG production (B) in subjects matched on visceral adipose tissue (VAT) volume with either normal or high intrahepatic triglyceride (IHTG) content and in subjects matched on IHTG content who had either low or high VAT volume. Values are means ± SEM. *, value is significantly different from corresponding value in the normal IHTG group, P < 0.001.

Fig. 3.

Skeletal muscle (A) and s.c. abdominal adipose tissue (C) CD36 gene expression and skeletal muscle (B) and adipose tissue CD36 protein content (D) in subjects matched on visceral adipose tissue (VAT) volume with either normal or high intrahepatic triglyceride (IHTG) content and in subjects matched on IHTG content who had either low or high VAT volume. Values are means ± SEM. *, value is significantly different from corresponding value in the normal IHTG group, P < 0.05.