Muscle Krüppel-like factor 15 regulates lipid flux and systemic metabolic homeostasis
Liyan Fan, … , Christopher B. Newgard, Mukesh K. Jain
Liyan Fan, … , Christopher B. Newgard, Mukesh K. Jain
Published February 15, 2021
Citation Information: J Clin Invest. 2021;131(4):e139496. https://doi.org/10.1172/JCI139496.
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Concise Communication Metabolism Muscle biology

Muscle Krüppel-like factor 15 regulates lipid flux and systemic metabolic homeostasis

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.

Authors

Liyan Fan, David R. Sweet, Domenick A. Prosdocimo, Vinesh Vinayachandran, Ernest R. Chan, Rongli Zhang, Olga Ilkayeva, Yuan Lu, Komal S. Keerthy, Chloe E. Booth, Christopher B. Newgard, Mukesh K. Jain

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Figure 2

K15-SKO mice exhibit exacerbated metabolic disease phenotype with HFD.

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K15-SKO mice exhibit exacerbated metabolic disease phenotype with HFD. (...
(A) Body weight (g) of animals on HFD starting from 8 weeks of age (n = 9–13). (B) IPGTT (n = 7–8). (C) IPITT at 10 weeks on HFD (n = 6–7). (D) Plasma insulin levels (n = 6–7). (E) Plasma triglyceride levels (n = 4–6). (F) Organ to body weight ratio of liver, kidney, and heart (n = 5–6). (G) Representative images of liver ORO staining in MyoCre vs. K15-SKO mice on HFD and quantification of proportional area of positive staining. (H) Liver tissue TG (n = 6–8). (I) Representative images of H&E-stained liver sections of MyoCre vs. K15-SKO mice. (J) Plasma alanine transaminase (ALT) concentration (n = 3–5). (K) Liver Cd36 expression (n = 4). (L) Expression of various inflammatory genes in liver tissue (n = 6–7). All animals were on HFD for 10 weeks unless otherwise indicated. Data represent mean ± SEM. Comparisons between MyoCre and K15-SKO mice were performed using an unpaired, 2-tailed Student’s t test, *P < 0.05, **P < 0.01, ***P < 0.001.