Impact of reduced ATGL-mediated adipocyte lipolysis on obesity-associated insulin resistance and inflammation in male mice

Gabriele Schoiswohl, Maja Stefanovic-Racic, Marie N. Menke, Rachel C. Wills, Beth A. Surlow, Mahesh K. Basantani, Mitchell Sitnick, Lingzhi Cai, Cynthia F. Yazbeck, Donna B. Stolz, Thomas Pulinilkunnil, Robert M. O'Doherty, Erin E. Kershaw

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Abstract

Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocytespecific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation,andexpression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.

Original languageEnglish
Pages (from-to)3610-3624
Number of pages15
JournalEndocrinology
Volume156
Issue number10
DOIs
StatePublished - 1 Oct 2015

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Lipolysis
Lipase
Adipocytes
Knockout Mice
Insulin Resistance
Adipose Tissue
Obesity
Inflammation
Diet
Lipids
Liver
Insulin
PPAR alpha
Adipogenesis
Adiponectin
Hepatocytes
Triglycerides
Hydrolysis
Body Weight
Phenotype

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Schoiswohl, G., Stefanovic-Racic, M., Menke, M. N., Wills, R. C., Surlow, B. A., Basantani, M. K., ... Kershaw, E. E. (2015). Impact of reduced ATGL-mediated adipocyte lipolysis on obesity-associated insulin resistance and inflammation in male mice. Endocrinology, 156(10), 3610-3624. https://doi.org/10.1210/en.2015-1322
Schoiswohl, Gabriele ; Stefanovic-Racic, Maja ; Menke, Marie N. ; Wills, Rachel C. ; Surlow, Beth A. ; Basantani, Mahesh K. ; Sitnick, Mitchell ; Cai, Lingzhi ; Yazbeck, Cynthia F. ; Stolz, Donna B. ; Pulinilkunnil, Thomas ; O'Doherty, Robert M. ; Kershaw, Erin E. / Impact of reduced ATGL-mediated adipocyte lipolysis on obesity-associated insulin resistance and inflammation in male mice. In: Endocrinology. 2015 ; Vol. 156, No. 10. pp. 3610-3624.
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abstract = "Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocytespecific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation,andexpression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.",
author = "Gabriele Schoiswohl and Maja Stefanovic-Racic and Menke, {Marie N.} and Wills, {Rachel C.} and Surlow, {Beth A.} and Basantani, {Mahesh K.} and Mitchell Sitnick and Lingzhi Cai and Yazbeck, {Cynthia F.} and Stolz, {Donna B.} and Thomas Pulinilkunnil and O'Doherty, {Robert M.} and Kershaw, {Erin E.}",
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Schoiswohl, G, Stefanovic-Racic, M, Menke, MN, Wills, RC, Surlow, BA, Basantani, MK, Sitnick, M, Cai, L, Yazbeck, CF, Stolz, DB, Pulinilkunnil, T, O'Doherty, RM & Kershaw, EE 2015, 'Impact of reduced ATGL-mediated adipocyte lipolysis on obesity-associated insulin resistance and inflammation in male mice', Endocrinology, vol. 156, no. 10, pp. 3610-3624. https://doi.org/10.1210/en.2015-1322

Impact of reduced ATGL-mediated adipocyte lipolysis on obesity-associated insulin resistance and inflammation in male mice. / Schoiswohl, Gabriele; Stefanovic-Racic, Maja; Menke, Marie N.; Wills, Rachel C.; Surlow, Beth A.; Basantani, Mahesh K.; Sitnick, Mitchell; Cai, Lingzhi; Yazbeck, Cynthia F.; Stolz, Donna B.; Pulinilkunnil, Thomas; O'Doherty, Robert M.; Kershaw, Erin E.

In: Endocrinology, Vol. 156, No. 10, 01.10.2015, p. 3610-3624.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Impact of reduced ATGL-mediated adipocyte lipolysis on obesity-associated insulin resistance and inflammation in male mice

AU - Schoiswohl, Gabriele

AU - Stefanovic-Racic, Maja

AU - Menke, Marie N.

AU - Wills, Rachel C.

AU - Surlow, Beth A.

AU - Basantani, Mahesh K.

AU - Sitnick, Mitchell

AU - Cai, Lingzhi

AU - Yazbeck, Cynthia F.

AU - Stolz, Donna B.

AU - Pulinilkunnil, Thomas

AU - O'Doherty, Robert M.

AU - Kershaw, Erin E.

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Schoiswohl G, Stefanovic-Racic M, Menke MN, Wills RC, Surlow BA, Basantani MK et al. Impact of reduced ATGL-mediated adipocyte lipolysis on obesity-associated insulin resistance and inflammation in male mice. Endocrinology. 2015 Oct 1;156(10):3610-3624. https://doi.org/10.1210/en.2015-1322