Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL-triglyceride kinetics

Abstract

Krag MB, Gormsen LC, Guo Z, Christiansen JS, Jensen MD, Nielsen S, Jørgensen JO. Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL-triglyceride kinetics. Am J Physiol Endocrinol Metab 292: E920 -E927, 2007. First published November 28, 2006; doi:10.1152/ajpendo.00374.2006.-The ability of growth hormone (GH) to stimulate lipolysis and cause insulin resistance in skeletal muscle may be causally linked, but the mechanisms remain obscure. We investigated the impact of GH on the turnover of FFA and VLDL-TG, intramuscular triglyceride content (IMTG), and insulin sensitivity (euglycemic clamp) in nine healthy men in a randomized double-blind placebo-controlled crossover study after 8 days treatment with (A) Placebo ϩ Placebo, (B) GH (2 mg daily) ϩ Placebo, and (C) GH (2 mg daily) ϩ Acipimox (250 mg ϫ 3 daily). In the basal state, GH (B) increased FFA levels (P Ͻ 0.05), palmitate turnover (P Ͻ 0.05), and lipid oxidation (P ϭ 0.05), but VLDL-TG kinetics were unaffected. Administration of acipimox (C) suppressed basal lipolysis but did not influence VLDL-TG kinetics. In the basal state, IMTG content increased after GH (B; P ϭ 0.03). Insulin resistance was induced by GH irrespective of concomitant acipimox (P Ͻ 0.001). The turnover of FFA and VLDL-TG was suppressed by hyperinsulinemia during placebo and GH, whereas coadministration of acipimox induced a rebound increase FFA turnover and VLDL-TG clearance. We conclude that these results show that GH-induced insulin resistance is associated with increased IMTG and unaltered VLDL-TG kinetics; we hypothesize that fat oxidation in muscle tissue is an important primary effect of GH and that circulating FFA rather than VLDL-TG constitute the major source for this process; and the role of IMTG in the development of GH-induced insulin resistance merits future research. acipimox; lipolysis; very-low-density lipoprotein-triglyceride kinetics; hyperinsulinemic euglycemic clamp; insulin sensitivity A REPRODUCIBLE EFFECT OF GROWTH HORMONE (GH) is mobilization of body fat and stimulation of lipid oxidation. Administration of a physiological GH bolus in the postabsorptive state increases circulating levels of free fatty acids (FFA) after a lag phase of 2 h, which is accompanied by suppression of the uptake and oxidation of glucose in skeletal muscle (35,36). Long-term GH administration translates into a significant reduction in fat mass, especially from the central compartments, and microdialysis studies demonstrate lipolysis directly in adipose tissue in vivo (10).The mechanisms underlying these effects of GH are not fully understood, but there is evidence to support that activation of the hormone-sensitive lipase is involved (9), and we (37) and others (41) have observed that coadministration of acipimox, a long-acting nicotinic acid analog, abrogates the GH-induced rise in FFA. Moreover, we have observed (38) that long-term administration of acipimox in GH-treated adult patients with GH deficiency did not af...

Follicle-stimulating hormone increases the intramuscular fat content and expression of lipid biosynthesis genes in chicken breast muscle

“…Our results are consistent with previous reports in chicken adipocytes (Cui et al, 2012) and mice adipocytes (Liu et al, 2015) that LPL mRNA was upregulated by FSH treatment. DGAT2 is the main enzyme that catalyzes the final step in the synthesis of TG, which involves esterification of fatty acids for conversion into TG before final storage in various adipose tissues (Krag et al, 2007;Yen et al, 2008). The results of our study showed that the FSH treatment group exhibited higher DGAT2 gene expression in chicken breast muscle and abdominal fat compared to controls, in agreement with similar results on DGAT2 gene expression by FSH stimulation in vitro (Cui et al, 2012).…”

Ten weeks of aerobic training does not result in persistent changes in VLDL triglyceride turnover or oxidation in healthy men

“…However, measurement of leg a-v differences, which was used in these studies, does not allow differentiation between increased storage of VLDL-TG in leg fat vs muscle tissue or to calculate oxidation, which therefore could explain some of the observed difference in leg clearance. Conversely, in a previous study, we reported that growth hormone infusion did not change VLDL oxidation in healthy adults although FFA levels and whole-body lipid oxidation were increased (42,43).…”

Lean body mass, not FFA, predicts VLDL-TG secretion rate in healthy men

“…This may also affect the VLDL particles rendering the use of steady-state kinetics impossible. In another study, no increase in VLDL-TG secretion was observed after elevating FFA levels with growth hormone (32). In both the present and a previous study (11), no association between FFA concentration or palmitate flux and VLDL-TG secretion was observed.…”