Abstract
Emerging evidence implicates ghrelin, a gut‐derived, orexigenic hormone, as a potential mediator of insulin‐responsive peripheral tissue metabolism. However, in vitro and in vivo studies assessing ghrelin's direct influence on metabolism have been controversial, particularly due to confounding factors such as the secondary rise in growth hormone (GH) after ghrelin injection. Skeletal muscle is important in the insulin‐stimulated clearance of glucose, and ghrelin's exponential rise prior to a meal could potentially facilitate this. This study was aimed at elucidating any direct stimulatory action that ghrelin may have on glucose transport and insulin signaling in isolated rat skeletal muscle, in the absence of confounding secondary factors. Oxidative soleus and glycolytic extensor digitorum longus skeletal muscles were isolated from male Sprague Dawley rats in the fed state and incubated with various concentrations of acylated and unacylated ghrelin in the presence or absence of insulin. Ghrelin did not stimulate glucose transport in either muscle type, with or without insulin. Moreover, GH had no acute, direct stimulatory effect on either basal or insulin‐stimulated muscle glucose transport. In agreement with the lack of observed effect on glucose transport, ghrelin and GH also had no stimulatory effect on Ser473 AKT or Thr172 AMPK phosphorylation, two key signaling proteins involved in glucose transport. Furthermore, to our knowledge, we are among the first to show that ghrelin can act independent of its receptor and cause an increase in calmodulin‐dependent protein kinase 2 (CaMKII) phosphorylation in glycolytic muscle, although this was not associated with an increase in glucose transport. We conclude that both acylated and unacylated ghrelin have no direct, acute influence on skeletal muscle glucose transport. Furthermore, the immediate rise in GH in response to ghrelin also does not appear to directly stimulate glucose transport in muscle.
Highlights
Ghrelin is a gut-derived hormone with central effects controlling appetite
It might be argued that ghrelin prevented insulin from stimulating glucose transport, this is complicated by the fact that none of the insulin conditions were statistically different from each other
While it is somewhat tenuous to state that ghrelin decreased insulin-stimulated glucose transport, our data are very clear that the ghrelin did not increase glucose transport, either in the presence or absence of insulin, which was the specific hypothesis that we were testing
Summary
Ghrelin is a gut-derived hormone with central effects controlling appetite. Its production and release increases exponentially prior to meals and returns to basal levels immediately postprandially (Kojima et al 1999; Liu et al 2008). Ghrelin can be posttranslationally acylated by ghrelin-O-acyl-transferase (GOAT) and unacylated by serum esterases (Gutierrez et al 2008; Yang et al 2008; Satou and Sugimoto 2012) It exists primarily unbound and unacylated, many of ghrelin’s effects can be attributed to its acylated form (Patterson et al 2005; Liu et al 2008). Ghrelin KO and ghrelin receptor KO mice are protected from the negative effects of a high fat diet on glucose tolerance and insulin sensitivity (Qi et al 2011). In contradiction to these a 2017 The Authors.
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