Ghrelin and the Regulation of Peripheral Tissue Metabolism
Authors: Cervone Daniel T , Dyck David J 
Published: November 2023

IntroductionGhrelin is a potent, appetite‐ and growth hormone (GH) ‐stimulating gastric hormone that has been recently shown to have important metabolic effects on insulin‐responsive peripheral tissues (eg. adipose tissue, skeletal muscle). Ghrelin increases exponentially prior to a meal, and rapidly declines to baseline after meal consumption. Therefore, it is important to elucidate any potential role that ghrelin may have in mediating carbohydrate and lipid metabolism surrounding entrained meal time. There is evidence, albeit limited, to suggest that both acylated (AG) and deacylated (DAG) ghrelin may act to potentiate glucose uptake in myocytes and inhibit the adrenergic stimulation of lipolysis in isolated adipocytes. Conversely, upon in vivo administration of ghrelin in humans, there is a marked decrease in insulin sensitivity and increases in local (adipose and skeletal muscle) indicators of lipolysis (glycerol). However, in vivo findings are confounded by factors such as the secondary increase in growth hormone, which can in itself stimulate lipolysis and influence glucose uptake.MethodsSoleus (oxidative) and extensor digitorum longus (EDL, glycolytic) muscles, and subcutaneous (inguinal ‐ iWAT) and visceral (retroperitoneal ‐ RP) adipose tissue depots were isolated from male Sprague Dawley rats. Muscles were incubated in the presence of labelled 3‐methyl‐O‐glucose to assess the effect of AG and DAG (5 to 150 nM) on basal and insulin stimulated glucose uptake. Adipose tissue organ culture was used to assess glycerol release (index of lipolysis) following incubation with either vehicle, the beta‐3 agonist CL 316 243 (10uM), CL + AG (50nM), CL + DAG (50nM) or AG and DAG independently.ResultsAG and DAG had a no direct influence on basal (Con: 62 ± 9; AG: 56 ± 5; DAG: 78 ± 13 nmol/g/5min) or insulin‐stimulated (Con: 41 ± 3; Ins: 82 ± 5; Ins+AG: 65 ± 11; Ins+DAG: 94 ± 9 nmol/g/5min) glucose uptake in soleus (shown) or EDL skeletal muscle. The activation of insulin signaling protein pAkt (Ser473) was also unchanged by ghrelin treatment. Compared to vehicle (iWAT: 0.54 ± 0.05; RP: 0.56 ± 0.08 mM/g) CL markedly increased rates of glycerol release in both iWAT (1.20 ± 0.06) and RP (1.91 ± 0.30) depots (p<0.05). This effect was abolished in the presence of both AG (iWAT: 0.79 ± 0.09; RP: 1.52 ± 0.12) and DAG (iWAT: 0.82 ± 0.05; RP: 1.44 ± 0.19) (p>0.05). AG (iWAT: 0.48 ± 0.08; RP: 0.54 ± 0.08) and DAG (iWAT: 0.62 ± 0.14; RP: 0.54 ± 0.09) did not independently affect glycerol release. These effects were observed following both 2h (shown) and 4h of treatment.ConclusionsGhrelin isoforms have no direct effect on skeletal muscle glucose uptake, but do inhibit adrenergic‐stimulated lipolysis in both subcutaneous and visceral adipose depots. Further work will consider whether ghrelin can act as a regulator of lipolysis in conjunction with other known pre and postprandial hormones (eg. GH, insulin). Finally, ghrelin action on cellular signaling underlying functional changes in lipolysis will be assessed (eg. HSL, ATGL, perilipin). These experiments will contribute to the accurate interpretation of AG and DAG's direct effects in peripheral tissue glucose and lipid metabolism.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada (NSERC).