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 4

SCFA-rich diet ameliorates lipid handling defects in K15-SKO mice.

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SCFA-rich diet ameliorates lipid handling defects in K15-SKO mice. (A) S...
(A) Schematic of prevention study pertaining to panels B–D depicting 8 weeks on either normal chow (NC) or SCFA-enriched diet followed by IPGTT/IPITT assessment. (B) Body weight of K15-SKO mice fed either NC or SCFA diet throughout 8 weeks of diet (n = 7–8). (C) IPGTT and (D) IPITT of K15-SKO mice fed either NC or SCFA (n = 5–7). (E) Schematic of therapy study pertaining to panels F–H depicting 5 weeks on HFD with IPGTT/IPITT, followed by 8 weeks of either NC or SCFA diet and IPGTT/IPITT. (F) Body weight of K15-SKO mice fed 5 weeks of HFD followed by NC or SCFA diet for an additional 8 weeks (n = 9–10). (G) IPGTT and (H) IPITT after 5 weeks of HFD and after an additional 8 weeks of NC or SCFA diet (n = 6–11). Data represent mean ± SEM. Comparisons between groups for panels B–D and F were performed using an unpaired, 2-tailed Student’s t test, *P < 0.05, **P < 0.01, ***P < 0.001. Comparisons between groups in panels F–H were performed using 1-way ANOVA with Tukey’s post hoc test, *P < 0.05 compared with HFD, #P < 0.05 compared with HFD+NC.