Age-related susceptibility to insulin resistance arises from a combination of CPT1B decline and lipid overload

BMC Biology

Ronald P. van Os¹  Rachel Thomas²  Marleen B. Dommerholt³  Johan W. Jonker³  Janine K. Kruit³  Marcel A. Vieira-Lara³  Barbara M. Bakker³  Maaike Blankestijn³  Fentaw Abegaz³  Dirk-Jan Reijngoud³  Ydwine T. van der Veen⁴  Justina C. Wolters⁴  Wenxuan Zhang⁴  Albert Gerding⁵ 

[1] Central Animal Facility, Mouse Clinic for Cancer and Aging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;Dutch Molecular Pathology Centre, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands;Laboratory of Pediatrics, Systems Medicine of Metabolism and Signaling, University Medical Center Groningen, University of Groningen, Postbus 196, 9700, Groningen, AD, The Netherlands;Laboratory of Pediatrics, Systems Medicine of Metabolism and Signaling, University Medical Center Groningen, University of Groningen, Postbus 196, 9700, Groningen, AD, The Netherlands;Department of Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands;Laboratory of Pediatrics, Systems Medicine of Metabolism and Signaling, University Medical Center Groningen, University of Groningen, Postbus 196, 9700, Groningen, AD, The Netherlands;Dutch Molecular Pathology Centre, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands;

关键词: Insulin resistance;    Skeletal muscle;    Mitochondrial β-oxidation;    Ageing;   

DOI  :  10.1186/s12915-021-01082-5

来源: Springer

【 摘 要 】

BackgroundThe skeletal muscle plays a central role in glucose homeostasis through the uptake of glucose from the extracellular medium in response to insulin. A number of factors are known to disrupt the normal response to insulin leading to the emergence of insulin resistance (IR). Advanced age and a high-fat diet are factors that increase the susceptibility to IR, with lipid accumulation in the skeletal muscle being a key driver of this phenomenon. It is debated, however, whether lipid accumulation arises due to dietary lipid overload or from a decline of mitochondrial function. To gain insights into the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we combined lipidomics, proteomics, mitochondrial function analysis and computational modelling to investigate young and aged mice on a low- or high-fat diet (HFD).ResultsAs expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals, glycolytic protein levels were reduced and less flexible to the diet.ConclusionWe conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their combined effects. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.

【 授权许可】

CC BY