Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic β3-adrenergic receptor activation

Emilio P. Mottillo; Priya Balasubramanian; Yun Hee Lee; Changren Weng; Erin E. Kershaw; James G. Granneman

doi:10.1194/jlr.M050005

Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic β3-adrenergic receptor activation

Emilio P. Mottillo, Priya Balasubramanian, Yun Hee Lee, Changren Weng, Erin E. Kershaw, James G. Granneman

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

174 Citations (Scopus)

Abstract

Chronic activation of β3-adrenergic receptors (β3-ARs) expands the catabolic activity of both brown and white adipose tissue by engaging uncoupling protein 1 (UCP1)-dependent and UCP1-independent processes. The present work examined de novo lipogenesis (DNL) and TG/glycerol dynamics in classic brown, subcutaneous "beige," and classic white adipose tissues during sustained β3-AR activation by CL 316,243 (CL) and also addressed the contribution of TG hydrolysis to these dynamics. CL treatment for 7 days dramatically increased DNL and TG turnover similarly in all adipose depots, despite great differences in UCP1 abundance. Increased lipid turnover was accompanied by the simultaneous upregulation of genes involved in FAS, glycerol metabolism, and FA oxidation. Inducible, adipocyte-specific deletion of adipose TG lipase (ATGL), the rate-limiting enzyme for lipolysis, demonstrates that TG hydrolysis is required for CL-induced increases in DNL, TG turnover, and mitochondrial electron transport in all depots. Interestingly, the effect of ATGL deletion on induction of specific genes involved in FA oxidation and synthesis varied among fat depots. Overall, these studies indicate that FAS and FA oxidation are tightly coupled in adipose tissues during chronic adrenergic activation, and this effect critically depends on the activity of adipocyte ATGL.

Original language	English
Pages (from-to)	2276-2286
Number of pages	11
Journal	Journal of Lipid Research
Volume	55
Issue number	11
DOIs	https://doi.org/10.1194/jlr.M050005
Publication status	Published - 2014

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grants DK092741 (J.G.G.), DK076229 (J.G.G.), DK062292 (J.G.G.), DK090166 (E.E.K.), and U24 DK76174 (Mouse Metabolic Phenotyping Center of Case Western Reserve University); a Howard Hughes Medical Institute Physician-Scientist Early Career Award (E.E.K.); and a Canadian Institutes of Health Research Doctoral Research Award MDR-214349 (E.P.M.).

Funding Information:
This work was supported by National Institutes of Health Grants DK092741 (J.G.G.), DK076229 (J.G.G.), DK062292 (J.G.G.), DK090166 (E.E.K.), and U24 DK76174 (Mouse Metabolic Phenotyping Center of Case Western Reserve University); a Howard Hughes Medical Institute Physician-Scientist Early Career Award (E.E.K.); and a Canadian Institutes of Health Research Doctoral Research Award MDR-214349 (E.P.M .). Manuscript received 7 April 2014 and in revised form 11 August 2014. Published, JLR Papers in Press, September 5, 2014 DOI 10.1194/jlr.M050005

Publisher Copyright:
Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

All Science Journal Classification (ASJC) codes

Biochemistry
Endocrinology
Cell Biology

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10.1194/jlr.M050005

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title = "Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic β3-adrenergic receptor activation",

abstract = "Chronic activation of β3-adrenergic receptors (β3-ARs) expands the catabolic activity of both brown and white adipose tissue by engaging uncoupling protein 1 (UCP1)-dependent and UCP1-independent processes. The present work examined de novo lipogenesis (DNL) and TG/glycerol dynamics in classic brown, subcutaneous {"}beige,{"} and classic white adipose tissues during sustained β3-AR activation by CL 316,243 (CL) and also addressed the contribution of TG hydrolysis to these dynamics. CL treatment for 7 days dramatically increased DNL and TG turnover similarly in all adipose depots, despite great differences in UCP1 abundance. Increased lipid turnover was accompanied by the simultaneous upregulation of genes involved in FAS, glycerol metabolism, and FA oxidation. Inducible, adipocyte-specific deletion of adipose TG lipase (ATGL), the rate-limiting enzyme for lipolysis, demonstrates that TG hydrolysis is required for CL-induced increases in DNL, TG turnover, and mitochondrial electron transport in all depots. Interestingly, the effect of ATGL deletion on induction of specific genes involved in FA oxidation and synthesis varied among fat depots. Overall, these studies indicate that FAS and FA oxidation are tightly coupled in adipose tissues during chronic adrenergic activation, and this effect critically depends on the activity of adipocyte ATGL.",

author = "Mottillo, {Emilio P.} and Priya Balasubramanian and Lee, {Yun Hee} and Changren Weng and Kershaw, {Erin E.} and Granneman, {James G.}",

note = "Funding Information: This work was supported by National Institutes of Health Grants DK092741 (J.G.G.), DK076229 (J.G.G.), DK062292 (J.G.G.), DK090166 (E.E.K.), and U24 DK76174 (Mouse Metabolic Phenotyping Center of Case Western Reserve University); a Howard Hughes Medical Institute Physician-Scientist Early Career Award (E.E.K.); and a Canadian Institutes of Health Research Doctoral Research Award MDR-214349 (E.P.M.). Funding Information: This work was supported by National Institutes of Health Grants DK092741 (J.G.G.), DK076229 (J.G.G.), DK062292 (J.G.G.), DK090166 (E.E.K.), and U24 DK76174 (Mouse Metabolic Phenotyping Center of Case Western Reserve University); a Howard Hughes Medical Institute Physician-Scientist Early Career Award (E.E.K.); and a Canadian Institutes of Health Research Doctoral Research Award MDR-214349 (E.P.M .). Manuscript received 7 April 2014 and in revised form 11 August 2014. Published, JLR Papers in Press, September 5, 2014 DOI 10.1194/jlr.M050005 Publisher Copyright: Copyright {\textcopyright} 2014 by the American Society for Biochemistry and Molecular Biology, Inc.",

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T1 - Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic β3-adrenergic receptor activation

AU - Mottillo, Emilio P.

AU - Balasubramanian, Priya

AU - Lee, Yun Hee

AU - Weng, Changren

AU - Kershaw, Erin E.

AU - Granneman, James G.

N1 - Funding Information: This work was supported by National Institutes of Health Grants DK092741 (J.G.G.), DK076229 (J.G.G.), DK062292 (J.G.G.), DK090166 (E.E.K.), and U24 DK76174 (Mouse Metabolic Phenotyping Center of Case Western Reserve University); a Howard Hughes Medical Institute Physician-Scientist Early Career Award (E.E.K.); and a Canadian Institutes of Health Research Doctoral Research Award MDR-214349 (E.P.M.). Funding Information: This work was supported by National Institutes of Health Grants DK092741 (J.G.G.), DK076229 (J.G.G.), DK062292 (J.G.G.), DK090166 (E.E.K.), and U24 DK76174 (Mouse Metabolic Phenotyping Center of Case Western Reserve University); a Howard Hughes Medical Institute Physician-Scientist Early Career Award (E.E.K.); and a Canadian Institutes of Health Research Doctoral Research Award MDR-214349 (E.P.M .). Manuscript received 7 April 2014 and in revised form 11 August 2014. Published, JLR Papers in Press, September 5, 2014 DOI 10.1194/jlr.M050005 Publisher Copyright: Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

PY - 2014

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N2 - Chronic activation of β3-adrenergic receptors (β3-ARs) expands the catabolic activity of both brown and white adipose tissue by engaging uncoupling protein 1 (UCP1)-dependent and UCP1-independent processes. The present work examined de novo lipogenesis (DNL) and TG/glycerol dynamics in classic brown, subcutaneous "beige," and classic white adipose tissues during sustained β3-AR activation by CL 316,243 (CL) and also addressed the contribution of TG hydrolysis to these dynamics. CL treatment for 7 days dramatically increased DNL and TG turnover similarly in all adipose depots, despite great differences in UCP1 abundance. Increased lipid turnover was accompanied by the simultaneous upregulation of genes involved in FAS, glycerol metabolism, and FA oxidation. Inducible, adipocyte-specific deletion of adipose TG lipase (ATGL), the rate-limiting enzyme for lipolysis, demonstrates that TG hydrolysis is required for CL-induced increases in DNL, TG turnover, and mitochondrial electron transport in all depots. Interestingly, the effect of ATGL deletion on induction of specific genes involved in FA oxidation and synthesis varied among fat depots. Overall, these studies indicate that FAS and FA oxidation are tightly coupled in adipose tissues during chronic adrenergic activation, and this effect critically depends on the activity of adipocyte ATGL.

AB - Chronic activation of β3-adrenergic receptors (β3-ARs) expands the catabolic activity of both brown and white adipose tissue by engaging uncoupling protein 1 (UCP1)-dependent and UCP1-independent processes. The present work examined de novo lipogenesis (DNL) and TG/glycerol dynamics in classic brown, subcutaneous "beige," and classic white adipose tissues during sustained β3-AR activation by CL 316,243 (CL) and also addressed the contribution of TG hydrolysis to these dynamics. CL treatment for 7 days dramatically increased DNL and TG turnover similarly in all adipose depots, despite great differences in UCP1 abundance. Increased lipid turnover was accompanied by the simultaneous upregulation of genes involved in FAS, glycerol metabolism, and FA oxidation. Inducible, adipocyte-specific deletion of adipose TG lipase (ATGL), the rate-limiting enzyme for lipolysis, demonstrates that TG hydrolysis is required for CL-induced increases in DNL, TG turnover, and mitochondrial electron transport in all depots. Interestingly, the effect of ATGL deletion on induction of specific genes involved in FA oxidation and synthesis varied among fat depots. Overall, these studies indicate that FAS and FA oxidation are tightly coupled in adipose tissues during chronic adrenergic activation, and this effect critically depends on the activity of adipocyte ATGL.

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Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic β3-adrenergic receptor activation

Abstract

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