Acylated ghrelin limits fat accumulation and improves redox state and inflammation markers in the liver of high-fat-fed rats.

OBJECTIVE: Obesity commonly causes hepatic lipid accumulation that may favor oxidative stress and inflammation with negative clinical impact. Acylated ghrelin (A-Ghr) modulates body lipid distribution and metabolism, and it may exert antioxidant effects in vitro as well as systemic anti-inflammatory effects in vivo. The impact of A-Ghr on liver triglyceride content, redox state and inflammation markers in diet-induced obesity was investigated. DESIGN AND METHODS: A-Ghr (200-µg/injection: HFG) or saline (HF) were administered subcutaneously twice-daily for 4 days to 12-week-old male rats fed a high-fat diet for 1 month (n = 8-10/group). RESULTS: Compared to lean animals, liver triglyceride accumulation occurred in HF despite enhanced phosphorylation of the lipid oxidation regulator AMPK and preserved mitochondrial enzyme activities. High triglycerides were accompanied by pro-oxidant changes in redox state and proinflammatory changes in NF-kB and TNF-alpha. A-Ghr limited liver triglyceride excess (P < 0.05 HF > HFG > Control) with concomitant activation of glutathione peroxidase and normalized redox state and cytokines. A-Ghr-induced liver changes were associated with higher plasma adiponectin and lower circulating fatty acids (P < 0.05 HFG vs. HF) CONCLUSIONS: A-Ghr limits liver triglyceride accumulation and normalizes tissue redox state and inflammation markers in diet-induced obese rats. These results suggest a favorable impact of A-Ghr on hepatic complications of diet-induced obesity.

Gastric bypass does not normalize obesity-related changes in ghrelin profile and leads to higher acylated ghrelin fraction.

OBJECTIVE: Gastric bypass (GBP) lowers food intake, body weight, and insulin resistance in severe obesity (SO). Ghrelin is a gastric orexigenic and adipogenic hormone contributing to modulate energy balance and insulin action. Total plasma ghrelin (T-Ghr) level is low and inversely related to body weight and insulin resistance in moderately obese patients, but these observations may not extend to the orexigenic acylated form (A-Ghr) whose plasma concentration increase in moderate obesity. DESIGN AND METHODS: We investigated the impact of GBP on plasma T-, A-, and A/T-Ghr in SO patients (n = 28, 20 women), with measurements at baseline and 1, 3, 6, and 12 months after surgery. Additional cross-sectional comparison was performed between nonobese, moderately obese, and SO individuals before GBP and at the end of the follow-up period. RESULTS: Before GBP, SO had lowest T-Ghr and highest A/T-Ghr profile compared with both nonobese and moderately obese individuals. Lack of early (0-3 months from GBP) T-Ghr changes masked a sharp increase in A-Ghr and A/T-Ghr profile (P < 0.05) that remained elevated following later increments (6-12 months) of both T- and A-Ghr (P < 0.05). Levels of A-Ghr and A/T-Ghr at 12 months of follow-up remained higher than in matched moderately obese individuals not treated with surgery (P < 0.05). CONCLUSIONS: The data show that following GBP, early T-Ghr stability masks elevation of A/T-Ghr, that is stabilized after later increments of both T- and A-hormones. GBP does not normalize the obesity-associated elevated A/T-Ghr ratio, instead resulting in enhanced A-Ghr excess. Excess A-Ghr is unlikely to contribute to, and might limit, the common GBP-induced declines of appetite, body weight, and insulin resistance.

Ghrelin enhances in vivo skeletal muscle but not liver AKT signaling in rats.

OBJECTIVE: Ghrelin administration can induce fat weight gain and hyperglycemia (potentially through ghrelin-induced hepatic glucose production), but plasma ghrelin is positively associated with whole-body insulin sensitivity (mainly reflecting muscle insulin action) being increased in lean individuals or after diet-induced weight loss and reduced in obesity or after diet-induced weight gain. To investigate potential mechanisms, we measured in vivo effects of sustained ghrelin administration at a non-orexigenic dose on skeletal muscle and liver insulin signaling at the AKT level and adipokine expression changes. RESEARCH METHODS AND PROCEDURES: Young-adult male rats received 4-day, twice daily subcutaneous ghrelin (200 mug/injection) or saline. We measured skeletal muscle (mixed, gastrocnemius; oxidative, soleus) and liver protein levels of activated [phosphorylated (P)] and total (T) AKT and glycogen synthase kinase (GSK; reflecting AKT-dependent GSK inactivation) and epididymal adipose tissue adipokine mRNA. RESULTS: Ghrelin increased body weight (+1.4%) and blood glucose (both p < 0.05 vs. saline) but not food intake, plasma insulin, or free fatty acids. Ghrelin, however, enhanced P/T/AKT and P/T/GSK ratios and glucose transporter-4 mRNA in soleus (p < 0.05), but not in gastrocnemius, muscle. In contrast, ghrelin reduced hepatic P/T-AKT and P/T-GSK. No alterations occurred in adiponectin, leptin, or resistin transcripts or plasma adiponectin. DISCUSSION: Despite moderate weight gain and in the absence of insulin-free fatty acid changes, sustained ghrelin administration enhanced oxidative muscle AKT activation. Reduced liver AKT signaling could potentially contribute to concomitant blood glucose increments. These findings support ghrelin as a novel tissue-specific modulator of lean tissue AKT signaling with insulin-sensitizing effects in skeletal muscle but not in liver in vivo.

Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution in liver and skeletal muscle.

Ghrelin is a gastric hormone increased during caloric restriction and fat depletion. A role of ghrelin in the regulation of lipid and energy metabolism is suggested by fat gain independent of changes in food intake during exogenous ghrelin administration in rodents. We investigated the potential effects of peripheral ghrelin administration (two times daily 200-micrograms [DOSAGE ERROR CORRECTED] sc injection for 4 days) on triglyceride content and mitochondrial and lipid metabolism gene expression in rat liver and muscles. Compared with vehicle, ghrelin increased body weight but not food intake and circulating insulin. In liver, ghrelin induced a lipogenic and glucogenic pattern of gene expression and increased triglyceride content while reducing activated (phosphorylated) stimulator of fatty acid oxidation, AMP-activated protein kinase (AMPK, all P < 0.05), with unchanged mitochondrial oxidative enzyme activities. In contrast, triglyceride content was reduced (P < 0.05) after ghrelin administration in mixed (gastrocnemius) and unchanged in oxidative (soleus) muscle. In mixed muscle, ghrelin increased (P < 0.05) mitochondrial oxidative enzyme activities independent of changes in expression of fat metabolism genes and phosphorylated AMPK. Expression of peroxisome proliferator-activated receptor-gamma, the activation of which reduces muscle fat content, was selectively increased in mixed muscle where it paralleled changes in oxidative capacities (P < 0.05). Thus ghrelin induces tissue-specific changes in mitochondrial and lipid metabolism gene expression and favors triglyceride deposition in liver over skeletal muscle. These novel effects of ghrelin in the regulation of lean tissue fat distribution and metabolism could contribute to metabolic adaptation to caloric restriction and loss of body fat.