Acyl Ghrelin Acts in the Brain to Control Liver Function and Peripheral Glucose Homeostasis in Male Mice

Abstract

Recent evidence suggests that peripheral ghrelin regulates glucose metabolism. Here, we designed experiments to examine how central acyl ghrelin infusion affects peripheral glucose metabolism under pair-fed or ad libitum feeding conditions. Mice received intracerebroventricular (icv) infusion of artificial cerebrospinal fluid (aCSF), ghrelin, and allowed to eat ad libitum (icv ghrelin ad lib) or ghrelin and pair-fed to the aCSF group (icv ghrelin pf). Minipumps delivered acyl ghrelin at a dose of 0.25 μg/h at 0.5 μL/h for 7 days. There was no difference in daily blood glucose, insulin, glucagon, triglycerides, or nonesterified fatty acids. Body weight gain and food intake was significantly higher in icv ghrelin ad lib mice. However, both icv ghrelin ad lib and icv ghrelin pf groups exhibited heavier white adipose mass. Icv ghrelin pf mice exhibited better glucose tolerance than aCSF or icv ghrelin ad lib mice during a glucose tolerance test, although both icv ghrelin ad lib and icv ghrelin pf increased insulin release during the glucose tolerance test. Central acyl ghrelin infusion and pair feeding also increased breakdown of liver glycogen and triglyceride, and regulated genes involved in hepatic lipid and glucose metabolism. Icv ghrelin pf mice had an increase in plasma blood glucose during a pyruvate tolerance test relative to icv ghrelin ad lib or aCSF mice. Our results suggest that under conditions of negative energy (icv ghrelin pf), central acyl ghrelin engages a neural circuit that influences hepatic glucose function. Metabolic status affects the ability of central acyl ghrelin to regulate peripheral glucose homeostasis.

Ghrelin modulates hypothalamic fatty acid-sensing and control of food intake in rainbow trout

“…injection changes in plasma glucose levels were noted (Schwandt et al 2010). Furthermore, the lack of changes in fatty acid levels is in agreement with that reported in mice under a comparable ICV treatment (Stark et al 2015). GHRL treatment did not affect levels of fatty acid, triglyceride or total lipid in the hypothalamus.…”

“…The orexigenic effect is in agreement with that observed in most fish species after IP or ICV GHRL treatments (Unniappan et al 2002, Tinoco et al 2014, and is in line to the effect of this peptide in other vertebrates, including mammals (Ló pez et al 2008, Sangiao-Alvarellos et al 2010, Velásquez et al 2011, Martins et al 2013, Stark et al 2015. It is surprising that GHRL did not also increase food intake 6 h after treatment.…”

“…The binding elicits an orexigenic response through enhanced stimulation of NPY/AgRP and decreased POMC/CART gene expression (Velásquez et al 2011). This orexigenic effect is mediated by changes in fatty acid metabolism and other parameters related to fatty acid-sensing systems that basically reverse those elicited by raised levels of LCFA (Ló pez et al 2008, Sangiao-Alvarellos et al 2010, Martins et al 2013, Gao et al 2013, Stark et al 2015. Besides the role of GHRL in food intake regulation, this hormone has been also involved in the control of glucose and lipid homeostasis and metabolism (Sangiao-Alvarellos et al 2010, Ratner et al 2015 and modulation of hormone release (Carreira et al 2013), among others (Sato et al 2014, Müller et al 2015.…”

Ghrelin deletion protects against age‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway

“…In another report, a low dose of ghrelin administered peripherally produced an increase in FAS and decreases in CPT‐1α mRNAs expression without affecting food intake. Although some reports have shown an increase in liver adiposity with ghrelin treatment (Davies et al ., 2009), others have shown the opposite effect with ghrelin preventing fat accumulation and improving redox state in the liver of high fat‐fed animals (Barazzoni et al ., 2013) but also under caloric restriction (Stark et al ., 2015). Additional factors may account for the differences in results reported by different groups: mouse age and strain, subchronic vs. chronic ghrelin treatment and via of administration (central vs. peripheral).…”

“…However, its role on hepatic steatosis is not known. Recent publications have suggested that it may increase liver adiposity through p53 signaling (Davies et al ., 2009; Porteiro et al ., 2013), although others have shown the opposite effect with ghrelin preventing fat accumulation and improving redox state in the liver of high fat‐fed animals (Barazzoni et al ., 2013) and also under pair‐feed conditions (Stark et al ., 2015). The goal of this work was to determine whether deletion of ghrelin might prevent the age‐associated NAFLD and to determine whether its effects are mediated through the p300‐C/EBPα/β pathway.…”