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Metabolic and tissue-specific regulation of acyl-CoA metabolism.

Ellis JM, Bowman CE, Wolfgang MJ - PLoS ONE (2015)

Bottom Line: We find patterns of coordinated regulation within and between these gene families as well as distinct regulation occurring in a tissue- and physiologically-dependent manner.Due to observed changes in long-chain ACOT mRNA and protein abundance in liver and adipose tissue, we determined the consequence of increasing cytosolic long-chain thioesterase activity on fatty acid metabolism in these tissues by generating transgenic mice overexpressing a hyperactive mutant of Acot7 in the liver or adipose tissue.Together, these data suggest distinct modes of regulation of the ACS and ACOT enzymes and that these enzymes act in a coordinated fashion to control fatty acid metabolism in a tissue-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Center for Metabolism and Obesity Research, Baltimore, Maryland 21205 United States of America.

ABSTRACT
Acyl-CoA formation initiates cellular fatty acid metabolism. Acyl-CoAs are generated by the ligation of a fatty acid to Coenzyme A mediated by a large family of acyl-CoA synthetases (ACS). Conversely, acyl-CoAs can be hydrolyzed by a family of acyl-CoA thioesterases (ACOT). Here, we have determined the transcriptional regulation of all ACS and ACOT enzymes across tissues and in response to metabolic perturbations. We find patterns of coordinated regulation within and between these gene families as well as distinct regulation occurring in a tissue- and physiologically-dependent manner. Due to observed changes in long-chain ACOT mRNA and protein abundance in liver and adipose tissue, we determined the consequence of increasing cytosolic long-chain thioesterase activity on fatty acid metabolism in these tissues by generating transgenic mice overexpressing a hyperactive mutant of Acot7 in the liver or adipose tissue. Doubling cytosolic acyl-CoA thioesterase activity failed to protect mice from diet-induced obesity, fatty liver or insulin resistance, however, overexpression of Acot7 in adipocytes rendered mice cold intolerant. Together, these data suggest distinct modes of regulation of the ACS and ACOT enzymes and that these enzymes act in a coordinated fashion to control fatty acid metabolism in a tissue-dependent manner.

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Increased adipocyte cytoplasmic long-chain acyl-CoA thioesterase activity inhibits cold-induced thermogenesis but does not protect against diet-induced obesity.A) Representative Acot7 western blot and (B) thioesterase activity for oleoyl-CoA in control and Acot7HA-Adi gonadal adipose (gWAT), inguinal adipose (iWAT), and brown adipose (BAT), n = 3–12. Control and Acot7HA-Adi (C) weight gain, (D) response to glucose tolerance test, and (E) inguinal and gonadal adipose weight in response to high-fat diet feeding for 11 weeks, n = 3–12. Control and Acot7HA-Adi (F) body temperature and (G) mRNA abundance of adrenergic genes in brown adipose in response to acute 4 hour cold (4°C) exposure, n = 8–10. Data represent mean ± SEM, * represent p≤0.05 by Student’s t-test.
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pone.0116587.g009: Increased adipocyte cytoplasmic long-chain acyl-CoA thioesterase activity inhibits cold-induced thermogenesis but does not protect against diet-induced obesity.A) Representative Acot7 western blot and (B) thioesterase activity for oleoyl-CoA in control and Acot7HA-Adi gonadal adipose (gWAT), inguinal adipose (iWAT), and brown adipose (BAT), n = 3–12. Control and Acot7HA-Adi (C) weight gain, (D) response to glucose tolerance test, and (E) inguinal and gonadal adipose weight in response to high-fat diet feeding for 11 weeks, n = 3–12. Control and Acot7HA-Adi (F) body temperature and (G) mRNA abundance of adrenergic genes in brown adipose in response to acute 4 hour cold (4°C) exposure, n = 8–10. Data represent mean ± SEM, * represent p≤0.05 by Student’s t-test.

Mentions: Adipose tissue expansion during obesity is a potential target to combat obesity and diabetes, therefore to determine if cytosolic thioesterase activity could reduce fatty acid accretion into adipocyte triglyceride to thwart the onset of diet-induced obesity and insulin resistance we expressed Acot7HA in adipose tissue specifically using the Adiponectin-Cre mouse (Acot7HA-Adi). The Acot7HA-Adi mice had ~2-fold greater long-chain thioesterase activity in visceral (gWAT), subcutaneous (iWAT), and brown adipose tissue (BAT) (Fig. 9A,B). The Acot7HA-Adi and littermate control mice were fed a high-fat (60%) diet for 12 weeks. The Acot7HA-Adi mice gained weight, responded to a glucose tolerance test, and accumulated adipose mass similar to their control littermates (Fig. 9C-E). Therefore, doubling adipose thioesterase activity was not sufficient to inhibit diet-induced obesity or insulin resistance.


Metabolic and tissue-specific regulation of acyl-CoA metabolism.

Ellis JM, Bowman CE, Wolfgang MJ - PLoS ONE (2015)

Increased adipocyte cytoplasmic long-chain acyl-CoA thioesterase activity inhibits cold-induced thermogenesis but does not protect against diet-induced obesity.A) Representative Acot7 western blot and (B) thioesterase activity for oleoyl-CoA in control and Acot7HA-Adi gonadal adipose (gWAT), inguinal adipose (iWAT), and brown adipose (BAT), n = 3–12. Control and Acot7HA-Adi (C) weight gain, (D) response to glucose tolerance test, and (E) inguinal and gonadal adipose weight in response to high-fat diet feeding for 11 weeks, n = 3–12. Control and Acot7HA-Adi (F) body temperature and (G) mRNA abundance of adrenergic genes in brown adipose in response to acute 4 hour cold (4°C) exposure, n = 8–10. Data represent mean ± SEM, * represent p≤0.05 by Student’s t-test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356623&req=5

pone.0116587.g009: Increased adipocyte cytoplasmic long-chain acyl-CoA thioesterase activity inhibits cold-induced thermogenesis but does not protect against diet-induced obesity.A) Representative Acot7 western blot and (B) thioesterase activity for oleoyl-CoA in control and Acot7HA-Adi gonadal adipose (gWAT), inguinal adipose (iWAT), and brown adipose (BAT), n = 3–12. Control and Acot7HA-Adi (C) weight gain, (D) response to glucose tolerance test, and (E) inguinal and gonadal adipose weight in response to high-fat diet feeding for 11 weeks, n = 3–12. Control and Acot7HA-Adi (F) body temperature and (G) mRNA abundance of adrenergic genes in brown adipose in response to acute 4 hour cold (4°C) exposure, n = 8–10. Data represent mean ± SEM, * represent p≤0.05 by Student’s t-test.
Mentions: Adipose tissue expansion during obesity is a potential target to combat obesity and diabetes, therefore to determine if cytosolic thioesterase activity could reduce fatty acid accretion into adipocyte triglyceride to thwart the onset of diet-induced obesity and insulin resistance we expressed Acot7HA in adipose tissue specifically using the Adiponectin-Cre mouse (Acot7HA-Adi). The Acot7HA-Adi mice had ~2-fold greater long-chain thioesterase activity in visceral (gWAT), subcutaneous (iWAT), and brown adipose tissue (BAT) (Fig. 9A,B). The Acot7HA-Adi and littermate control mice were fed a high-fat (60%) diet for 12 weeks. The Acot7HA-Adi mice gained weight, responded to a glucose tolerance test, and accumulated adipose mass similar to their control littermates (Fig. 9C-E). Therefore, doubling adipose thioesterase activity was not sufficient to inhibit diet-induced obesity or insulin resistance.

Bottom Line: We find patterns of coordinated regulation within and between these gene families as well as distinct regulation occurring in a tissue- and physiologically-dependent manner.Due to observed changes in long-chain ACOT mRNA and protein abundance in liver and adipose tissue, we determined the consequence of increasing cytosolic long-chain thioesterase activity on fatty acid metabolism in these tissues by generating transgenic mice overexpressing a hyperactive mutant of Acot7 in the liver or adipose tissue.Together, these data suggest distinct modes of regulation of the ACS and ACOT enzymes and that these enzymes act in a coordinated fashion to control fatty acid metabolism in a tissue-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Center for Metabolism and Obesity Research, Baltimore, Maryland 21205 United States of America.

ABSTRACT
Acyl-CoA formation initiates cellular fatty acid metabolism. Acyl-CoAs are generated by the ligation of a fatty acid to Coenzyme A mediated by a large family of acyl-CoA synthetases (ACS). Conversely, acyl-CoAs can be hydrolyzed by a family of acyl-CoA thioesterases (ACOT). Here, we have determined the transcriptional regulation of all ACS and ACOT enzymes across tissues and in response to metabolic perturbations. We find patterns of coordinated regulation within and between these gene families as well as distinct regulation occurring in a tissue- and physiologically-dependent manner. Due to observed changes in long-chain ACOT mRNA and protein abundance in liver and adipose tissue, we determined the consequence of increasing cytosolic long-chain thioesterase activity on fatty acid metabolism in these tissues by generating transgenic mice overexpressing a hyperactive mutant of Acot7 in the liver or adipose tissue. Doubling cytosolic acyl-CoA thioesterase activity failed to protect mice from diet-induced obesity, fatty liver or insulin resistance, however, overexpression of Acot7 in adipocytes rendered mice cold intolerant. Together, these data suggest distinct modes of regulation of the ACS and ACOT enzymes and that these enzymes act in a coordinated fashion to control fatty acid metabolism in a tissue-dependent manner.

Show MeSH
Related in: MedlinePlus