Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels.

M. Bosma, M.K.C. Hesselink, L.M. Sparks, S. Timmers, M.J. Ferraz, F. Mattijssen, D. Van Beurden, G. Schaart, M.H.V. de Baets, F.K. Verheyen, S. Kersten, P. Schrauwen

Research output: Contribution to journalArticleAcademicpeer-review

49 Citations (Scopus)

Abstract

Type 2 diabetes is characterized by excessive lipid storage in skeletal muscle. Excessive intramyocellular lipid (IMCL) storage exceeds intracellular needs and induces lipotoxic events, ultimately contributing to the development of insulin resistance. Lipid droplet (LD)-coating proteins may control proper lipid storage in skeletal muscle. Perilipin 2 (PLIN2/adipose differentiation-related protein [ADRP]) is one of the most abundantly expressed LD-coating proteins in skeletal muscle. Here we examined the role of PLIN2 in myocellular lipid handling and insulin sensitivity by investigating the effects of in vitro PLIN2 knockdown and in vitro and in vivo overexpression. PLIN2 knockdown decreased LD formation and triacylglycerol (TAG) storage, marginally increased fatty-acid (FA) oxidation, and increased incorporation of palmitate into diacylglycerols and phospholipids. PLIN2 overexpression in vitro increased intramyocellular TAG storage paralleled with improved insulin sensitivity. In vivo muscle-specific PLIN2 overexpression resulted in increased LD accumulation and blunted the high-fat diet-induced increase in protein content of the subunits of the oxidative phosphorylation (OXPHOS) chain. Diacylglycerol levels were unchanged, whereas ceramide levels were increased. Despite the increased IMCL accumulation, PLIN2 overexpression improved skeletal muscle insulin sensitivity. We conclude that PLIN2 is essential for lipid storage in skeletal muscle by enhancing the partitioning of excess FAs toward TAG storage in LDs, thereby blunting lipotoxicity-associated insulin resistance.
Original languageEnglish
Pages (from-to)2679-2690
Number of pages12
JournalDiabetes
Volume61
Issue number11
DOIs
Publication statusPublished - Nov 2012

Keywords

  • DIFFERENTIATION-RELATED PROTEIN
  • TRIGLYCERIDE LIPASE
  • ADRP EXPRESSION
  • DEFICIENT MICE
  • FATTY-ACIDS
  • LIVER-CELLS
  • RESISTANCE
  • DROPLETS
  • TRIACYLGLYCEROL
  • ACCUMULATION

Cite this

Bosma, M. ; Hesselink, M.K.C. ; Sparks, L.M. ; Timmers, S. ; Ferraz, M.J. ; Mattijssen, F. ; Van Beurden, D. ; Schaart, G. ; de Baets, M.H.V. ; Verheyen, F.K. ; Kersten, S. ; Schrauwen, P. / Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels. In: Diabetes. 2012 ; Vol. 61, No. 11. pp. 2679-2690.
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title = "Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels.",
abstract = "Type 2 diabetes is characterized by excessive lipid storage in skeletal muscle. Excessive intramyocellular lipid (IMCL) storage exceeds intracellular needs and induces lipotoxic events, ultimately contributing to the development of insulin resistance. Lipid droplet (LD)-coating proteins may control proper lipid storage in skeletal muscle. Perilipin 2 (PLIN2/adipose differentiation-related protein [ADRP]) is one of the most abundantly expressed LD-coating proteins in skeletal muscle. Here we examined the role of PLIN2 in myocellular lipid handling and insulin sensitivity by investigating the effects of in vitro PLIN2 knockdown and in vitro and in vivo overexpression. PLIN2 knockdown decreased LD formation and triacylglycerol (TAG) storage, marginally increased fatty-acid (FA) oxidation, and increased incorporation of palmitate into diacylglycerols and phospholipids. PLIN2 overexpression in vitro increased intramyocellular TAG storage paralleled with improved insulin sensitivity. In vivo muscle-specific PLIN2 overexpression resulted in increased LD accumulation and blunted the high-fat diet-induced increase in protein content of the subunits of the oxidative phosphorylation (OXPHOS) chain. Diacylglycerol levels were unchanged, whereas ceramide levels were increased. Despite the increased IMCL accumulation, PLIN2 overexpression improved skeletal muscle insulin sensitivity. We conclude that PLIN2 is essential for lipid storage in skeletal muscle by enhancing the partitioning of excess FAs toward TAG storage in LDs, thereby blunting lipotoxicity-associated insulin resistance.",
keywords = "DIFFERENTIATION-RELATED PROTEIN, TRIGLYCERIDE LIPASE, ADRP EXPRESSION, DEFICIENT MICE, FATTY-ACIDS, LIVER-CELLS, RESISTANCE, DROPLETS, TRIACYLGLYCEROL, ACCUMULATION",
author = "M. Bosma and M.K.C. Hesselink and L.M. Sparks and S. Timmers and M.J. Ferraz and F. Mattijssen and {Van Beurden}, D. and G. Schaart and {de Baets}, M.H.V. and F.K. Verheyen and S. Kersten and P. Schrauwen",
year = "2012",
month = "11",
doi = "10.2337/db11-1402",
language = "English",
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Bosma, M, Hesselink, MKC, Sparks, LM, Timmers, S, Ferraz, MJ, Mattijssen, F, Van Beurden, D, Schaart, G, de Baets, MHV, Verheyen, FK, Kersten, S & Schrauwen, P 2012, 'Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels.', Diabetes, vol. 61, no. 11, pp. 2679-2690. https://doi.org/10.2337/db11-1402

Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels. / Bosma, M.; Hesselink, M.K.C.; Sparks, L.M.; Timmers, S.; Ferraz, M.J.; Mattijssen, F.; Van Beurden, D.; Schaart, G.; de Baets, M.H.V.; Verheyen, F.K.; Kersten, S.; Schrauwen, P.

In: Diabetes, Vol. 61, No. 11, 11.2012, p. 2679-2690.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels.

AU - Bosma, M.

AU - Hesselink, M.K.C.

AU - Sparks, L.M.

AU - Timmers, S.

AU - Ferraz, M.J.

AU - Mattijssen, F.

AU - Van Beurden, D.

AU - Schaart, G.

AU - de Baets, M.H.V.

AU - Verheyen, F.K.

AU - Kersten, S.

AU - Schrauwen, P.

PY - 2012/11

Y1 - 2012/11

N2 - Type 2 diabetes is characterized by excessive lipid storage in skeletal muscle. Excessive intramyocellular lipid (IMCL) storage exceeds intracellular needs and induces lipotoxic events, ultimately contributing to the development of insulin resistance. Lipid droplet (LD)-coating proteins may control proper lipid storage in skeletal muscle. Perilipin 2 (PLIN2/adipose differentiation-related protein [ADRP]) is one of the most abundantly expressed LD-coating proteins in skeletal muscle. Here we examined the role of PLIN2 in myocellular lipid handling and insulin sensitivity by investigating the effects of in vitro PLIN2 knockdown and in vitro and in vivo overexpression. PLIN2 knockdown decreased LD formation and triacylglycerol (TAG) storage, marginally increased fatty-acid (FA) oxidation, and increased incorporation of palmitate into diacylglycerols and phospholipids. PLIN2 overexpression in vitro increased intramyocellular TAG storage paralleled with improved insulin sensitivity. In vivo muscle-specific PLIN2 overexpression resulted in increased LD accumulation and blunted the high-fat diet-induced increase in protein content of the subunits of the oxidative phosphorylation (OXPHOS) chain. Diacylglycerol levels were unchanged, whereas ceramide levels were increased. Despite the increased IMCL accumulation, PLIN2 overexpression improved skeletal muscle insulin sensitivity. We conclude that PLIN2 is essential for lipid storage in skeletal muscle by enhancing the partitioning of excess FAs toward TAG storage in LDs, thereby blunting lipotoxicity-associated insulin resistance.

AB - Type 2 diabetes is characterized by excessive lipid storage in skeletal muscle. Excessive intramyocellular lipid (IMCL) storage exceeds intracellular needs and induces lipotoxic events, ultimately contributing to the development of insulin resistance. Lipid droplet (LD)-coating proteins may control proper lipid storage in skeletal muscle. Perilipin 2 (PLIN2/adipose differentiation-related protein [ADRP]) is one of the most abundantly expressed LD-coating proteins in skeletal muscle. Here we examined the role of PLIN2 in myocellular lipid handling and insulin sensitivity by investigating the effects of in vitro PLIN2 knockdown and in vitro and in vivo overexpression. PLIN2 knockdown decreased LD formation and triacylglycerol (TAG) storage, marginally increased fatty-acid (FA) oxidation, and increased incorporation of palmitate into diacylglycerols and phospholipids. PLIN2 overexpression in vitro increased intramyocellular TAG storage paralleled with improved insulin sensitivity. In vivo muscle-specific PLIN2 overexpression resulted in increased LD accumulation and blunted the high-fat diet-induced increase in protein content of the subunits of the oxidative phosphorylation (OXPHOS) chain. Diacylglycerol levels were unchanged, whereas ceramide levels were increased. Despite the increased IMCL accumulation, PLIN2 overexpression improved skeletal muscle insulin sensitivity. We conclude that PLIN2 is essential for lipid storage in skeletal muscle by enhancing the partitioning of excess FAs toward TAG storage in LDs, thereby blunting lipotoxicity-associated insulin resistance.

KW - DIFFERENTIATION-RELATED PROTEIN

KW - TRIGLYCERIDE LIPASE

KW - ADRP EXPRESSION

KW - DEFICIENT MICE

KW - FATTY-ACIDS

KW - LIVER-CELLS

KW - RESISTANCE

KW - DROPLETS

KW - TRIACYLGLYCEROL

KW - ACCUMULATION

U2 - 10.2337/db11-1402

DO - 10.2337/db11-1402

M3 - Article

VL - 61

SP - 2679

EP - 2690

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 11

ER -