Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes

Laffel, Lori M.

doi:10.1002/(sici)1520-7560(199911/12)15:6<412::aid-dmrr72>3.0.co;2-8

Cited by 1,177 publications

(1,155 citation statements)

References 105 publications

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“…Collectively, these findings support the notion that AA is capable of functioning as a signaling molecule in regulating muscle cell function. Interestingly, recent reports have demonstrated that abnormally accumulated fumarate plays a novel role in the irregular modification of cellular proteins (succination of KEAP1) and Nrf2 (NFE2-related factor 2) signaling in fumarate hydratase-deficient cells and that these functions are independent of its ability to inhibit ␣-ketoglutarate-dependent dioxygenases (17,(73)(74)(75). Thus, our findings and the results of prior studies collectively indicate that AA could regulate cellular activity independent of its energetic role.…”

Section: Discussionsupporting

confidence: 71%

“…AA and 3HB are both prominent ketone bodies that serve as energy-rich compounds to transport energy from the liver to other tissues, particularly the brain and skeletal muscle (41,73). However, AA differs from 3HB in that it also has unique functions in various biological processes, such as insulin release in vitro, generation of free oxygen radicals, lipid peroxidation, and activation of the ERK1/2 and p38 MAPK signaling pathways (45,46,49).…”

Section: Discussionmentioning

confidence: 99%

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Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Zou

Meng

et al. 2016

Journal of Biological Chemistry

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Acetoacetate (AA) is a ketone body and acts as a fuel to supply energy for cellular activity of various tissues. Here, we uncovered a novel function of AA in promoting muscle cell proliferation. Notably, the functional role of AA in regulating muscle cell function is further evidenced by its capability to accelerate muscle regeneration in normal mice, and it ameliorates muscular dystrophy in mdx mice. Mechanistically, our data from multiparameter analyses consistently support the notion that AA plays a non-metabolic role in regulating muscle cell function. Finally, we show that AA exerts its function through activation of the MEK1-ERK1/2-cyclin D1 pathway, revealing a novel mechanism in which AA serves as a signaling metabolite in mediating muscle cell function. Our findings highlight the profound functions of a small metabolite as signaling molecule in mammalian cells.Satellite cells, which are among the most abundant well defined adult stem cell types in skeletal muscle, play functionally important roles in postnatal growth, repair, and the regeneration of skeletal muscle (1-6). Because of their powerful ability to regenerate in vivo in response to muscle damage and various stimuli, satellite cells represent important targets for the treatment of muscular diseases (7-10). The recent development of stem cell-based regenerative medicine strategies has brought enormous interest in the discovery of regulatory factors capable of controlling satellite cell functions, such as activation, proliferation, differentiation, and self-renewal (11-13). Identification of such factors is expected to not only improve our understanding of the regulatory mechanisms that govern satellite cell functions, but also to facilitate the development of stem cell-based therapies for the treatment of muscular dystrophy or other chronic diseases associated with muscle wasting.Recent studies demonstrating a close correlation between cell proliferation and metabolic alterations in various tumor types have drawn attention to the significance of intrinsic small metabolites as signaling molecules responsible for regulating various cellular activities (14, 15). Although only a very limited number of such metabolites have been identified to date, accumulating evidence suggests that these metabolites can be oncogenic and alter cell signaling through epigenetic regulation. For example, 2-hydroxyglutarate (2-HG), 4 succinate, and fumarate, which are the best characterized small metabolites with oncogenic function, have come to be regarded as oncometabolites (16 -19). In tumor cells, 2-HG is generated by mutant forms of isocitrate dehydrogenase (IDH1 and IDH2) (20 -23), whereas succinate and fumarate accumulate via mutant forms of succinate dehydrogenase and fumarate hydratase, respectively (24 -27). It has been clearly demonstrated that increases in the levels of these oncometabolites play causal roles in tumorigenesis (26 -34). Recent studies of the molecular mechanisms underlying their action have revealed that 2-HG and elevated levels of succinate ...

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Zou

Meng

et al. 2016

Journal of Biological Chemistry

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“…2) Mitochondrial succinyl-CoA:3-ketoacid CoA transferase (SCOT; EC 2.8.3.5) is the enzyme thought to be responsible for ketone body utilization for energy production 3) and to be essential for energy balance. 4) On the other hand, recent studies have shown that ketone bodies are directly activated in the cytosol by a novel acetoacetate-specific ligase, acetoacetyl-CoA synthetase (AACS, acetoacetate-CoA ligase, EC 6.2.1.16), for the synthesis of physiologically important lipidic substances such as cholesterol and fatty acid.…”

mentioning

confidence: 99%

The Role of Acetoacetyl-CoA Synthetase, a Ketone Body-Utilizing Enzyme, in 3T3-L1 Adipocyte Differentiation

Hasegawa

Ikeda

Yamasaki

et al. 2012

Biological & Pharmaceutical Bulletin

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Acetoacetyl-CoA synthetase (AACS) is a ketone body-utilizing enzyme that converts acetoacetate to acetoacetyl-CoA in the cytosol and consequently provides acetyl units as the precursors for lipogenesis. To clarify the role of AACS in adipogenesis, we investigated the expression and localization of the AACS protein and the effect of AACS knockdown on 3T3-L1 differentiation. The protein expression of AACS is dramatically induced during 3T3-L1 differentiation and is localized in the cytoplasm of differentiated 3T3-L1 cells. Moreover, knockdown of AACS inhibits differentiation of 3T3-L1 cells and suppresses expression of the adipocyte markers, peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα). These results suggest that AACS has a crucial role in the mechanism of 3T3-L1 differentiation.

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“…In fact, some degree of carbohydrate intolerance had been reported previously for lean WKY rats, although on that occasion rats were still not fully inbred (Ikeda et al 1981, Kava et al 1990. Furthermore, the very high levels of circulating b-hydroxybutyrate, one of the main ketone bodies produced by the liver, determined in the plasma of STDfed WKY rats supported this non-predominant oxidative glucose utilisation (McGarry & Foster 1980, Laffel 1999. Moreover, the disparity observed between the circulating levels of ketone bodies in STD-and CAF-fed WKY rats may be an indication that the source of the dietary carbohydrates plays a key role in carbohydrate metabolism, as has been previously described for other rat strains (Michaelis et al 1986).…”

Section: Discussionmentioning

confidence: 71%

Leptin signal transduction underlies the differential metabolic response of LEW and WKY rats to cafeteria diet

Martínez-Micaelo

González-Abuín

Ardévol

et al. 2015

Journal of Molecular Endocrinology

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Although the effect of genetic background on obesity-related phenotypes is well established, the main objective of this study is to determine the phenotypic responses to cafeteria diet (CAF) of two genetically distinct inbred rat strains and give insight into the molecular mechanisms that might be underlying. Lewis (LEW) and Wistar-Kyoto (WKY) rats were fed with either a standard or a CAF diet. The effects of the diet and the strain in the body weight gain, food intake, respiratory quotient, biochemical parameters in plasma as well as in the expression of genes that regulate leptin signalling were determined. Whereas CAF diet promoted weight gain in LEW and WKY rats, as consequence of increased energy intake, metabolic management of this energy surplus was significantly affected by genetic background. LEW and WKY showed a different metabolic profile, LEW rats showed hyperglycaemia, hypertriglyceridemia and high FFA levels, ketogenesis, high adiposity index and inflammation, but WKY did not. Leptin signalling, and specifically the LepRb-mediated regulation of STAT3 activation and Socs3 gene expression in the hypothalamus were inversely modulated by the CAF diet in LEW (upregulated) and WKY rats (downregulated). In the present study, we show evidence of gene-environment interactions in obesity exerted by differential phenotypic responses to CAF diet between LEW and WKY rats. Specifically, we found the leptin-signalling pathway as a divergent point between the strain-specific adaptations to diet.

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Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes

Cited by 1,177 publications

References 105 publications

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

The Role of Acetoacetyl-CoA Synthetase, a Ketone Body-Utilizing Enzyme, in 3T3-L1 Adipocyte Differentiation

Leptin signal transduction underlies the differential metabolic response of LEW and WKY rats to cafeteria diet

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