Ghrelin is classically known as a central appetite‐stimulating hormone but has recently been recognized to have a significant role in peripheral tissue energy metabolism. However, the direct effects of ghrelin on skeletal muscle, a major site for glucose and lipid disposal, remain understudied. We found that the two major ghrelin isoforms, acylated and unacylated ghrelin, were able to significantly increase skeletal muscle fatty acid oxidation (~20%) while incorporation of fatty acids into major lipid pools remained unchanged. The increase in fatty acid oxidation was accompanied by increases in acetyl‐CoA carboxylase phosphorylation, a downstream target of AMPK . Ghrelin isoforms had no independent effect on lipolysis under unstimulated conditions, but nearly completely abolished epinephrine‐stimulated lipolysis. This effect was generally, but not consistently related to a blunting in the phosphorylation of HSL activation sites, Ser660 and 563. Taken together, these findings suggest that ghrelin isoforms have a direct, acute effect on fatty acid oxidation and lipolysis.
Ghrelin has garnered interest as a gut-derived regulator of lipid metabolism, beyond its classical roles in driving appetite and growth hormone release. Ghrelin's circulating concentrations follow an ultradian rhythm, peak immediately before a meal and point towards a potential metabolic role in reducing the mobilization of fatty acid stores in preparation for the storage of ingested food. Here, we demonstrate that both acylated and unacylated ghrelin have physiological roles in attenuating lipolysis in mature subcutaneous and visceral adipose tissue depots of rats. Ghrelin blunted the ß3-induction (CL 316, 243) of glycerol release (index of lipolysis) which coincided with a reduced activation of the key lipid hydrolase HSL at two of its serine residues (Ser 563 / 660). Furthermore, ghrelin appeared to inhibit fatty acid reesterification in the presence of CL such that fatty acid concentrations in the surrounding media were maintained in spite of a reduction in lipolysis. Importantly, these aforementioned effects were not observed following ghrelin injection in vivo, as there was no attenuation of CL-induced glycerol release. This highlights the importance of exercising caution when interpreting the effects of administering ghrelin in vivo, and the necessity for uncovering the elusive mechanisms by which ghrelin regulates lipolysis and fatty acid reesterification. We conclude that both acylated and unacylated ghrelin can exert direct inhibitory effects on lipolysis and fatty acid reesterification in adipose tissue from rats. However, these effects are not observed in vivo and outline the complexity of studying ghrelin's effects on fatty acid metabolism in the living animal.
IntroductionThe Chiari II is a relatively common birth defect that is associated with open spinal abnormalities and is characterized by caudal migration of the posterior fossa contents through the foramen magnum. The pathophysiology of Chiari II is not entirely known, and the neurobiological substrate beyond posterior fossa findings remains unexplored. We aimed to identify brain regions altered in Chiari II fetuses between 17 and 26 GW.MethodsWe used in vivo structural T2-weighted MRIs of 31 fetuses (6 controls and 25 cases with Chiari II).ResultsThe results of our study indicated altered development of diencephalon and proliferative zones (ventricular and subventricular zones) in fetuses with a Chiari II malformation compared to controls. Specifically, fetuses with Chiari II showed significantly smaller volumes of the diencephalon and significantly larger volumes of lateral ventricles and proliferative zones.DiscussionWe conclude that regional brain development should be taken into consideration when evaluating prenatal brain development in fetuses with Chiari II.
Ghrelin is classically known as a central appetite stimulating hormone, but has recently been recognized to have a significant role in peripheral tissue energy metabolism. Given that ghrelin rapidly increases prior to entrained mealtimes, it is possible that ghrelin may act as part of a preparatory response to facilitate the metabolism of ingested glucose and lipids. Skeletal muscle is a major site for glucose and lipid disposal; however, the direct effects of ghrelin on this tissue remain understudied. Furthermore, studies examining the metabolic effects of in vivo ghrelin injections fail to distinguish independent effects of ghrelin from secondary effects such as increases in growth hormone. Therefore, the purpose of this study was to determine the direct effects of the two main isoforms of ghrelin, acylated (AG) and unacylated (UnAG) on fatty acid (FA) metabolism in isolated rat skeletal muscle. Specifically, we examined the effect of ghrelin (AG, UnAG) on labeled palmitate oxidation and incorporation into major lipid pools (diacylglycerol, DAG; triacylglycerol, TAG) under conditions of low glucose (5 mM) or high glucose concentrations (10 mM). Soleus (SOL) and extensor digitorum longus (EDL) were used as representative oxidative and glycolytic muscles and 1mM palmitate was used in the medium throughout. We hypothesized that ghrelin would facilitate the uptake of fatty acids into skeletal muscle thereby increasing oxidation and incorporation into lipid pools. SOL and EDL muscle strips were excised from male Sprague‐Dawley rats (~250 g) and incubated with either 150 ng/ml of AG or UnAG, or 2 mM of 5‐Aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), a known stimulant of fatty acid oxidation (positive control). To assess oxidation, sulfuric acid was added directly to the medium containing the muscle to release14CO2, which was trapped in a suspended vial containing benzethonium hydroxide. In a separate set of experiments, 14C palmitate incorporation into muscle lipid pools was assessed by extracting lipids into a 2:1 chloroform:methanol solution and spotting on a thin layer chromatography plate. A repeated measures one‐way ANOVA uncorrected for Fisher's LSD was performed and significance was accepted at p≤0.05. In agreement with our hypothesis, both isoforms of ghrelin (AG and UnAG) stimulated palmitate oxidation. At 10 mM glucose, both AG and UnAG increased palmitate oxidation (~40%; p<0.05) in SOL and EDL. At the lower glucose concentration (5 mM), UnAG increased palmitate oxidation (SOL, 41%; EDL, 27%; p<0.05); and a near significant trend of AG induced FA oxidation was observed in EDL (23%; p=0.07), but not in SOL (14%, p=0.258). Deposition of labeled fatty acids into DAG and TAG pools was unaffected by AG and UnAG, suggesting that the acute effect of ghrelin on muscle is solely directed at oxidation. In summary, ghrelin has a direct, acute stimulatory effect on fatty acid metabolism in both oxidative and glycolytic skeletal muscle. This effect appears to be directed only at oxidation, and occurs regardless of the glucose environment. Further experiments will be performed to assess the effect of ghrelin on fat breakdown (lipolysis) in muscle and the underlying cellular signaling mechanisms involved.Support or Funding InformationNSERCThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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