Enhancing hepatic mitochondrial fatty acid oxidation stimulates eating in food-deprived mice

Hepatic fatty acid oxidation (FAO) has long been implicated in the control of eating. Nevertheless, direct evidence for a causal relationship between changes in hepatic FAO and changes in food intake is still missing. Here we tested whether increasing hepatic FAO via adenovirus-mediated expression of a mutated form of the key regulatory enzyme of mitochondrial FAO carnitine palmitoyltransferase 1A (CPT1mt), which is active but insensitive to inhibition by malonyl-CoA, affects eating and metabolism in mice. CPT1mt expression increased hepatocellular CPT1 protein levels. This resulted in an increase in circulating ketone body levels in fasted CPT1mt-expressing mice, suggesting an increase in hepatic FAO. These mice did not show any significant changes in cumulative food intake, energy expenditure, or respiratory quotient after 4-h food deprivation. After 24-h food deprivation, however, the CPT1mt-expressing mice displayed increased food intake. Thus expression of CPT1mt in the liver increases hepatic FAO capacity, but does not inhibit eating. Rather, it may even stimulate eating after prolonged food deprivation. These data do not support the hypothesis that an increase in hepatic FAO decreases food intake.

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tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine palmitoyltransferase-1

Cell Death and Differentiation ◽

10.1038/sj.cdd.4401636 ◽

2005 ◽

Vol 12 (6) ◽

pp. 603-613 ◽

Cited By ~ 45

Author(s):

A Giordano ◽

M Calvani ◽

O Petillo ◽

P Grippo ◽

F Tuccillo ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Carnitine Palmitoyltransferase ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Malonyl Coa ◽

Mitochondrial Fatty Acid ◽

Carnitine Palmitoyltransferase 1

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SOCS2 Inhibits Mitochondrial Fatty Acid Oxidation via Suppressing LepR/JAK2/AMPK Signaling Pathway in Mouse Adipocytes

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3742542 ◽

2020 ◽

Vol 2020 ◽

pp. 1-21 ◽

Cited By ~ 1

Author(s):

Tiantian Zhang ◽

Yizhe Chen ◽

Jiarui Cai ◽

Miao Pan ◽

Qian Sun ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Nervous System Development ◽

Cytokine Signaling ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Protein Levels ◽

Ampk Pathway ◽

Mitochondrial Fatty Acid

Suppressor of cytokine signaling 2 (SOCS2) plays an important role in fat deposition, skeletal muscle, central nervous system development, and mitochondria biogenesis. Nevertheless, the regulatory mechanisms of SOCS2 on mitochondrial fatty acid oxidation (FAO) remain unclear. Leptin could inhibit food intake and increase thermogenesis through leptin receptor (LepR), which was present in the hypothalamus and certain peripheral organs, including adipose tissue. With strong interest, we focused on the connection between leptin and SOCS2 and their effect on FAO in adipocytes. In our study, we found that the mRNA level of SOCS2 and the protein levels of PGC-1α, CPT-1b, FAT, and p-ACC were elevated by leptin in the inguinal adipose tissue of mice. On the contrary, the protein levels of FABP4, FATP1, and FAS were declined. The genes related to fatty acid oxidation such as PGC-1α, NRF-1, TFAM, CPT-1b, AOX1, COX2, and UCP2 were attenuated by SOCS2, but elevated by leptin. Moreover, fatty acid oxidation enzyme MCAD, LCAD, and Cyt C levels were reduced in response to SOCS2. These reductions correspond well with the reduced release of free fatty acid and the reduction of mitochondrial complexes I and III by SOCS2. Furthermore, JAK2/AMPK pathway-specific inhibitors could block the mitochondrial FAO; hence, this pathway was implied to have a potential impact on FAO. Together, these studies suggested that SOCS2 had a negative effect on mitochondrial fatty acid oxidation, and the LepR/JAK2/AMPK pathway played a crucial role in this process.

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Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart

Journal of Biological Chemistry ◽

10.1074/jbc.m400162200 ◽

2004 ◽

Vol 279 (19) ◽

pp. 19574-19579 ◽

Cited By ~ 52

Author(s):

Aneta E. Reszko ◽

Takhar Kasumov ◽

France David ◽

Kathryn A. Jobbins ◽

Katherine R. Thomas ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Acetyl Coa ◽

Mitochondrial Fatty Acid Oxidation ◽

Fatty Acid Chain ◽

Rat Hearts ◽

Malonyl Coa ◽

Mitochondrial Fatty Acid ◽

Perfused Rat Hearts

Little is known about the sources of acetyl-CoA used for the synthesis of malonyl-CoA, a key regulator of mitochondrial fatty acid oxidation in the heart. In perfused rat hearts, we previously showed that malonyl-CoA is labeled from both carbohydrates and fatty acids. This study was aimed at assessing the mechanisms of incorporation of fatty acid carbons into malonyl-CoA. Rat hearts were perfused with glucose, lactate, pyruvate, and a fatty acid (palmitate, oleate or docosanoate). In each experiment, substrates were13C-labeled to yield singly or/and doubly labeled acetyl-CoA. The mass isotopomer distribution of malonyl-CoA was compared with that of the acetyl moiety of citrate, which reflects mitochondrial acetyl-CoA. In the presence of labeled glucose or lactate/pyruvate, the13C labeling of malonyl-CoA was up to 2-fold lower than that of mitochondrial acetyl-CoA. However, in the presence of a fatty acid labeled in its first acetyl moiety, the13C labeling of malonyl-CoA was up to 10-fold higher than that of mitochondrial acetyl-CoA. The labeling of malonyl-CoA and of the acetyl moiety of citrate is compatible with peroxisomal β-oxidation forming C12and C14acyl-CoAs and contributing >50% of the fatty acid-derived acetyl groups that end up in malonyl-CoA. This fraction increases with the fatty acid chain length. By supplying acetyl-CoA for malonyl-CoA synthesis, peroxisomal β-oxidation may participate in the control of mitochondrial fatty acid oxidation in the heart. In addition, this pathway may supply some acyl groups used in protein acylation, which is increasingly recognized as an important regulatory mechanism for many biochemical processes.

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Peroxisomal oxidation of erucic acid suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation in the rat liver

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013583 ◽

2020 ◽

Vol 295 (30) ◽

pp. 10168-10179 ◽

Cited By ~ 1

Author(s):

Xiaocui Chen ◽

Lin Shang ◽

Senwen Deng ◽

Ping Li ◽

Kai Chen ◽

...

Keyword(s):

Fatty Acid ◽

Erucic Acid ◽

Hepatic Steatosis ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Acetyl Coa ◽

Mitochondrial Fatty Acid Oxidation ◽

High Erucic Acid ◽

Malonyl Coa ◽

Mitochondrial Fatty Acid

Feeding of rapeseed (canola) oil with a high erucic acid concentration is known to cause hepatic steatosis in animals. Mitochondrial fatty acid oxidation plays a central role in liver lipid homeostasis, so it is possible that hepatic metabolism of erucic acid might decrease mitochondrial fatty acid oxidation. However, the precise mechanistic relationship between erucic acid levels and mitochondrial fatty acid oxidation is unclear. Using male Sprague–Dawley rats, along with biochemical and molecular biology approaches, we report here that peroxisomal β-oxidation of erucic acid stimulates malonyl-CoA formation in the liver and thereby suppresses mitochondrial fatty acid oxidation. Excessive hepatic uptake and peroxisomal β-oxidation of erucic acid resulted in appreciable peroxisomal release of free acetate, which was then used in the synthesis of cytosolic acetyl-CoA. Peroxisomal metabolism of erucic acid also remarkably increased the cytosolic NADH/NAD+ ratio, suppressed sirtuin 1 (SIRT1) activity, and thereby activated acetyl-CoA carboxylase, which stimulated malonyl-CoA biosynthesis from acetyl-CoA. Chronic feeding of a diet including high-erucic-acid rapeseed oil diminished mitochondrial fatty acid oxidation and caused hepatic steatosis and insulin resistance in the rats. Of note, administration of a specific peroxisomal β-oxidation inhibitor attenuated these effects. Our findings establish a cross-talk between peroxisomal and mitochondrial fatty acid oxidation. They suggest that peroxisomal oxidation of long-chain fatty acids suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation, which might play a role in fatty acid–induced hepatic steatosis and related metabolic disorders.

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Changes in the activities of the enzymes of hepatic fatty acid oxidation during development of the rat

Biochemical Journal ◽

10.1042/bj1540049 ◽

1976 ◽

Vol 154 (1) ◽

pp. 49-56 ◽

Cited By ~ 35

Author(s):

P C Foster ◽

E Bailey

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Outer Mitochondrial Membrane ◽

Mitochondrial Fatty Acid Oxidation ◽

Carnitine Acyltransferase ◽

Mitochondrial Fatty Acid ◽

Foetal Life ◽

Hydroxyacyl Coa Dehydrogenase ◽

Hepatic Fatty Acid Oxidation

1. Changes in the activities of several enzymes involved in mitochondrial fatty acid oxidation were measured in livers of developing rats between late foetal life and maturity. The enzymes studied are medium- and long-chain ATP-dependent acyl-CoA synthetases of the outer mitochondrial membrane and matrix, GTP-dependent acyl-CoA synthetase, carnitine acyltransferase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, general 3-oxoacyl-CoA thiolase and acetoacetyl-CoA thiolase.

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l-carnitine acyltransferase in intact peroxisomes is inhibited by malonyl-CoA

Biochemical Journal ◽

10.1042/bj2620801 ◽

1989 ◽

Vol 262 (3) ◽

pp. 801-806 ◽

Cited By ~ 52

Author(s):

J P Derrick ◽

R R Ramsay

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Marker Enzyme ◽

Mitochondrial Enzyme ◽

Mitochondrial Fatty Acid Oxidation ◽

Peroxisomal Enzyme ◽

Carnitine Acyltransferase ◽

Malonyl Coa ◽

Mitochondrial Fatty Acid

Inhibition of the overt mitochondrial carnitine palmitoyltransferase by malonyl-CoA is important in the regulation of fatty acid oxidation. In the past, the contribution of peroxisomal carnitine acyltransferase activity to the generation of medium- and long-chain acylcarnitines in the cytoplasm has been ignored. On the basis of marker enzyme levels, we now estimate that peroxisomal palmitoyltransferase activity constitutes about 20% of the peroxisomal plus overt-mitochondrial pool in fed rat liver. When assayed in situ, both the palmitoyltransferase and decanoyltransferase activities of gradient-purified peroxisomes are sensitive to malonyl-CoA, with up to 90% inhibition reached at less than 10 microM-malonyl-CoA. Very similar results were obtained with intact gradient-purified mitochondria from the same livers. In addition, the acyl-CoA substrate chain-length specificity was identical in both the peroxisomes and the mitochondria, with a decanoyltransferase/palmitoyltransferase ratio of 2. Thus the overt carnitine acyltransferase activities in peroxisomes and mitochondria have the same properties. Further, the malonyl-CoA sensitivity of the peroxisomal activity is lost on solubilization, as has been observed for the overt mitochondrial enzyme. It is suggested that malonyl-CoA inhibition of the peroxisomal enzyme as well as of the mitochondrial enzyme is important for the regulation of mitochondrial fatty acid oxidation.

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