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Muscle Krüppel-like factor 15 regulates lipid flux and systemic metabolic
Authors Fan L, Sweet DR, Prosdocimo DA, Vinayachandran V, Chan ER, Zhang R, Ilkayeva O,
Lu Y, Keerthy KS, Booth CE, Newgard CB, Jain MK
Submitted By Submitted Externally on 2/22/2021
Status Published
Journal The Journal of clinical investigation
Year 2021
Date Published 2/1/2021
Volume : Pages 131 : Not Specified
PubMed Reference 33586679
Abstract Skeletal muscle is a major determinant of systemic metabolic homeostasis that
plays a critical role in glucose metabolism and insulin sensitivity. By
contrast, despite being a major user of fatty acids, and evidence that muscular
disorders can lead to abnormal lipid deposition (e.g., nonalcoholic fatty liver
disease in myopathies), our understanding of skeletal muscle regulation of
systemic lipid homeostasis is not well understood. Here we show that skeletal
muscle Krüppel-like factor 15 (KLF15) coordinates pathways central to systemic
lipid homeostasis under basal conditions and in response to nutrient overload.
Mice with skeletal muscle-specific KLF15 deletion demonstrated (a) reduced
expression of key targets involved in lipid uptake, mitochondrial transport, and
utilization, (b) elevated circulating lipids, (c) insulin resistance/glucose
intolerance, and (d) increased lipid deposition in white adipose tissue and
liver. Strikingly, a diet rich in short-chain fatty acids bypassed these defects
in lipid flux and ameliorated aspects of metabolic dysregulation. Together,
these findings establish skeletal muscle control of lipid flux as critical to
systemic lipid homeostasis and metabolic health.


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