Myostatin induces insulin resistance via Casitas B-lineage lymphoma b (Cblb)-mediated degradation of insulin receptor substrate 1 (IRS1) protein in response to high calorie diet intake.
To date a plethora of evidence has clearly demonstrated that continued high calorie intake leads to insulin resistance and type-2 diabetes with or without obesity. However, the necessary signals that initiate insulin resistance during high calorie intake remain largely unknown. Our results here show that in response to a regimen of high fat or high glucose diets, Mstn levels were induced in muscle and liver of mice. High glucose- or fat-mediated induction of Mstn was controlled at the level of transcription, as highly conserved carbohydrate response and sterol-responsive (E-box) elements were present in the Mstn promoter and were revealed to be critical for ChREBP (carbohydrate-responsive element-binding protein) or SREBP1c (sterol regulatory element-binding protein 1c) regulation of Mstn expression. Further molecular analysis suggested that the increased Mstn levels (due to high glucose or fatty acid loading) resulted in increased expression of Cblb in a Smad3-dependent manner. Casitas B-lineage lymphoma b (Cblb) is an ubiquitin E3 ligase that has been shown to specifically degrade insulin receptor substrate 1 (IRS1) protein. Consistent with this, our results revealed that elevated Mstn levels specifically up-regulated Cblb, resulting in enhanced ubiquitin proteasome-mediated degradation of IRS1. In addition, over expression or knock down of Cblb had a major impact on IRS1 and pAkt levels in the presence or absence of insulin. Collectively, these observations strongly suggest that increased glucose levels and high fat diet, both, result in increased circulatory Mstn levels. The increased Mstn in turn is a potent inducer of insulin resistance by degrading IRS1 protein via the E3 ligase, Cblb, in a Smad3-dependent manner.
From the School of Biological Sciences, Nanyang Technological University, Singapore 637551.
Sabeera
S
Bonala
Sudarsanareddy
S
Lokireddy
Craig
C
McFarlane
Sreekanth
S
Patnam
Mridula
M
Sharma
Ravi
R
Kambadur
D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D004041:Dietary Fats / Q000008:administration & dosage; D005786:Gene Expression Regulation; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D016086:Lentivirus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D055435:Myostatin / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010168:Palmitates / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose; D004041:Dietary Fats; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C506001:Mlxipl protein, mouse; D055435:Myostatin; D009687:Nuclear Proteins; D010168:Palmitates; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D050721:Proto-Oncogene Proteins c-cbl; C493849:Cbl protein, mouse; D005947:Glucose
Cblb; Diabetes; High Fat Diet; High Glucose; IRS1; Insulin Resistance; Myostatin; Signaling; Skeletal Muscle; Skeletal Muscle Metabolism