Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics

Wendy S. Hahn, Jovan Kuzmicic, Joel S. Burrill, Margaret A. Donoghue, Rocio Foncea, Michael Dennis Jensen, Sergio Lavandero, Edgar A. Arriaga, David A. Bernlohr

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Macrophage infiltration of adipose tissue and the chronic low-grade production of inflammatory cytokines have been mechanistically linked to the development of insulin resistance, the forerunner of type 2 diabetes mellitus. In this study, we evaluated the chronic effects of TNFα, IL-6, and IL-1β on adipocyte mitochondrial metabolism and morphology using the 3T3-L1 model cell system. TNFα treatment of cultured adipocytes led to significant changes in mitochondrial bioenergetics, including increased proton leak, decreased ΔΨm, increased basal respiration, and decreased ATP turnover. In contrast, although IL-6 and IL-1β decreased maximal respiratory capacity, they had no effect on ΔΨm and varied effects on ATP turnover, proton leak, or basal respiration. Only TNFα treatment of 3T3-L1 cells led to an increase in oxidative stress (as measured by superoxide anion production and protein carbonylation) and C16 ceramide synthesis. Treatment of 3T3-L1 adipocytes with cytokines led to decreased mRNA expression of key transcription factors and control proteins implicated in mitochondrial biogenesis, including PGC-1α and eNOS as well as deceased expression of COX IV and Cyt C. Whereas each cytokine led to effects on expression of mitochondrial markers, TNFα exclusively led to mitochondrial fragmentation and decreased the total level of OPA1 while increasing OPA1 cleavage, without expression of levels of mitofusin 2, DRP-1, or mitofilin being affected. In summary, these results indicate that inflammatory cytokines have unique and specialized effects on adipocyte metabolism, but each leads to decreased mitochondrial function and a reprogramming of fat cell biology.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume306
Issue number9
DOIs
StatePublished - May 1 2014

Fingerprint

Adipocytes
Oxidative Stress
Cytokines
3T3-L1 Cells
Interleukin-1
Protons
Interleukin-6
Respiration
Adenosine Triphosphate
Protein Carbonylation
Organelle Biogenesis
Superoxides
Type 2 Diabetes Mellitus
Energy Metabolism
Cell Biology
Insulin Resistance
Adipose Tissue
Transcription Factors
Therapeutics
Macrophages

Keywords

  • Adipocyte
  • Cytokine
  • Fusion
  • Mitochondria
  • Respiration

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. / Hahn, Wendy S.; Kuzmicic, Jovan; Burrill, Joel S.; Donoghue, Margaret A.; Foncea, Rocio; Jensen, Michael Dennis; Lavandero, Sergio; Arriaga, Edgar A.; Bernlohr, David A.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 306, No. 9, 01.05.2014.

Research output: Contribution to journalArticle

Hahn, Wendy S. ; Kuzmicic, Jovan ; Burrill, Joel S. ; Donoghue, Margaret A. ; Foncea, Rocio ; Jensen, Michael Dennis ; Lavandero, Sergio ; Arriaga, Edgar A. ; Bernlohr, David A. / Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. In: American Journal of Physiology - Endocrinology and Metabolism. 2014 ; Vol. 306, No. 9.
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AU - Jensen, Michael Dennis

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AB - Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Macrophage infiltration of adipose tissue and the chronic low-grade production of inflammatory cytokines have been mechanistically linked to the development of insulin resistance, the forerunner of type 2 diabetes mellitus. In this study, we evaluated the chronic effects of TNFα, IL-6, and IL-1β on adipocyte mitochondrial metabolism and morphology using the 3T3-L1 model cell system. TNFα treatment of cultured adipocytes led to significant changes in mitochondrial bioenergetics, including increased proton leak, decreased ΔΨm, increased basal respiration, and decreased ATP turnover. In contrast, although IL-6 and IL-1β decreased maximal respiratory capacity, they had no effect on ΔΨm and varied effects on ATP turnover, proton leak, or basal respiration. Only TNFα treatment of 3T3-L1 cells led to an increase in oxidative stress (as measured by superoxide anion production and protein carbonylation) and C16 ceramide synthesis. Treatment of 3T3-L1 adipocytes with cytokines led to decreased mRNA expression of key transcription factors and control proteins implicated in mitochondrial biogenesis, including PGC-1α and eNOS as well as deceased expression of COX IV and Cyt C. Whereas each cytokine led to effects on expression of mitochondrial markers, TNFα exclusively led to mitochondrial fragmentation and decreased the total level of OPA1 while increasing OPA1 cleavage, without expression of levels of mitofusin 2, DRP-1, or mitofilin being affected. In summary, these results indicate that inflammatory cytokines have unique and specialized effects on adipocyte metabolism, but each leads to decreased mitochondrial function and a reprogramming of fat cell biology.

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