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Ghrelin Causes a Decline in GABA Release by Reducing Fatty Acid Oxidation in Cortex.

ABSTRACT: Lipid metabolism, specifically fatty acid oxidation (FAO) mediated by carnitine palmitoyltransferase (CPT) 1A, has been described to be an important actor of ghrelin action in hypothalamus. However, it is not known whether CPT1A and FAO mediate the effect of ghrelin on the cortex. Here, we show that ghrelin produces a differential effect on CPT1 activity and γ-aminobutyric acid (GABA) metabolism in the hypothalamus and cortex of mice. In the hypothalamus, ghrelin enhances CPT1A activity while GABA transaminase (GABAT) activity, a key enzyme in GABA shunt metabolism, is unaltered. However, in cortex CPT1A activity and GABAT activity are reduced after ghrelin treatment. Furthermore, in primary cortical neurons, ghrelin reduces GABA release through a CPT1A reduction. By using CPT1A floxed mice, we have observed that genetic ablation of CPT1A recapitulates the effect of ghrelin on GABA release in cortical neurons, inducing reductions in mitochondrial oxygen consumption, cell content of citrate and α-ketoglutarate, and GABA shunt enzyme activity. Taken together, these observations indicate that ghrelin-induced changes in CPT1A activity modulate mitochondrial function, yielding changes in GABA metabolism. This evidence suggests that the action of ghrelin on GABA release is region specific within the brain, providing a basis for differential effects of ghrelin in the central nervous system.

SUBMITTER: Mir JF

PROVIDER: S-EPMC6096967 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Ghrelin Causes a Decline in GABA Release by Reducing Fatty Acid Oxidation in Cortex.

Mir Joan Francesc JF Zagmutt Sebastián S Lichtenstein Mathieu P MP García-Villoria Judit J Weber Minéia M Gracia Ana A Fabriàs Gemma G Casas Josefina J López Miguel M Casals Núria N Ribes Antònia A Suñol Cristina C Herrero Laura L Serra Dolors D

Molecular neurobiology 20180202 9

Lipid metabolism, specifically fatty acid oxidation (FAO) mediated by carnitine palmitoyltransferase (CPT) 1A, has been described to be an important actor of ghrelin action in hypothalamus. However, it is not known whether CPT1A and FAO mediate the effect of ghrelin on the cortex. Here, we show that ghrelin produces a differential effect on CPT1 activity and γ-aminobutyric acid (GABA) metabolism in the hypothalamus and cortex of mice. In the hypothalamus, ghrelin enhances CPT1A activity while GA ...[more]

PMID: 29396649

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Project description:Background & aimsNon-alcoholic fatty liver disease (NAFLD) affects nearly a quarter of the population with no approved pharmacological therapy. Liver steatosis is a primary characteristic of NAFLD. Recent studies suggest that human umbilical cord mesenchymal stem cell-derived exosomes (MSC-ex) may provide a promising strategy for treating liver injury; however, the role and underlying mechanisms of MSC-ex in steatosis are not fully understood.MethodsOleic-palmitic acid-treated hepatic cells and high-fat diet (HFD)-induced NAFLD mice were established to observe the effect of MSC-ex. Using non-targeted lipidomics and transcriptome analyses, we analysed the gene pathways positively correlated with MSC-ex. Mass spectrometry and gene knockdown/overexpression analyses were performed to evaluate the effect of calcium/calmodulin-dependent protein kinase 1 (CAMKK1) transferred by MSC-ex on lipid homoeostasis regulation.ResultsHere, we demonstrate that MSC-ex promote fatty acid oxidation and reduce lipogenesis in oleic-palmitic acid-treated hepatic cells and HFD-induced NAFLD mice. Non-targeted lipidomics and transcriptome analyses suggested that the effect of MSC-ex on lipid accumulation positively correlated with the phosphorylation of AMP-activated protein kinase. Furthermore, mass spectrometry and gene knockdown/overexpression analyses revealed that MSC-ex-transferred CAMKK1 is responsible for ameliorating lipid accumulation in an AMP-activated protein kinase-dependent manner, which subsequently inhibits SREBP-1C-mediated fatty acid synthesis and enhances peroxisome proliferator-activated receptor alpha (PPARα)-mediated fatty acid oxidation.ConclusionsMSC-ex may prevent HFD-induced NAFLD via CAMKK1-mediated lipid homoeostasis regulation.Impact and implicationsNAFLD includes many conditions, from simple steatosis to non-alcoholic steatohepatitis, which can lead to fibrosis, cirrhosis, and even hepatocellular carcinoma. So far, there is no approved drug for treating liver steatosis of NAFLD. Thus, better therapies are needed to regulate lipid metabolism and prevent the progression from liver steatosis to chronic liver disease. By using a combination of non-targeted lipidomic and transcriptome analyses, we revealed that human umbilical cord mesenchymal stem cell-derived exosomes (MSC-ex) effectively reduced lipid deposition and improved liver function from HFD-induced liver steatosis. Our study highlights the importance of exosomal CAMKK1 from MSC-ex in mediating lipid metabolism regulation via AMPK-mediated PPARα/CPT-1A and SREBP-1C/fatty acid synthase signalling in hepatocytes. These findings are significant in elucidating novel mechanisms related to MSC-ex-based therapies for preventing NAFLD.

Project description:Germline mutations of TP53, which cause the cancer predisposition disorder Li-Fraumeni syndrome (LFS), can increase mitochondrial activity as well as fatty acid β-oxidation (FAO) in mice. Increased fatty acid metabolism can promote cancer malignancy, but its specific contribution to tumorigenesis in LFS remains unclear. To investigate this, we crossed LFS mice carrying the p53 R172H knock-in mutation (p53172H/H , homolog of the human TP53 R175H LFS mutation) with myoglobin-knockout (MB-/- ) mice known to have decreased FAO. MB-/- p53172H/H double-mutant mice also showed mildly reduced FAO in thymus, a common site of T lymphoma development in LFS mice, in association with an approximately 40% improvement in cancer-free survival time. RNA sequencing profiling revealed that the p53 R172H mutation promotes mitochondrial metabolism and ribosome biogenesis, both of which are suppressed by the disruption of MB. The activation of ribosomal protein S6, involved in protein translation and implicated in cancer promotion, was also inhibited in the absence of MB. To further confirm the role of FAO in lymphomagenesis, mitochondrial FAO enzyme, carnitine palmitoyltransferase 2 (CPT2), was specifically disrupted in T cells of p53172H/H mice using a Cre-loxP-mediated strategy. The heterozygous knockout of CPT2 resulted in thymus FAO haploinsufficiency and an approximately 30% improvement in survival time, paralleling the antiproliferative signaling observed with MB disruption. Thus, this study demonstrates that moderating FAO in LFS can suppress tumorigenesis and improve cancer-free survival with potential implications for cancer prevention. PREVENTION RELEVANCE: Mildly inhibiting the increased fatty acid oxidation observed in a mouse model of Li-Fraumeni syndrome, a cancer predisposition disorder caused by inherited mutations of TP53, dampens aberrant pro-tumorigenic cell signaling and improves the survival time of these mice, thereby revealing a potential strategy for cancer prevention in patients.

Dataset Information

Ghrelin Causes a Decline in GABA Release by Reducing Fatty Acid Oxidation in Cortex.

Publications

Ghrelin Causes a Decline in GABA Release by Reducing Fatty Acid Oxidation in Cortex.

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