Fig 1.
Systemic KLF15 is required for the heart’s functional adaptation in response to fasting.
(A) Left ventricular fractional shortening from echocardiography performed in wild-type (WT) vs. systemic Klf15-null (Klf15-/-) under fed vs. 48 hours fasting conditions, (n = 5), *P,0.05 vs. WT Fast. (B) Representative echocardiography image from WT vs. Klf15-/- following a 48 hour fast. (C) Tabular representation of echocardiography data in WT vs. Klf15-/- under fed vs. 48 hour fasting conditions.
Fig 2.
Cardiac KLF15 is required for the heart’s functional adaptation in response to fasting.
(A) Left ventricular fractional shortening from echocardiography performed in control (MHC-Cre) vs KLF15-cKO under fed vs. 48 hours fasting conditions, (n = 5), *P<0.05 vs. MHC-Cre Fast. (B) Representative echocardiography image from MHC-Cre vs. KLF15-cKO following a 48 hour fast. (C) Tabular representation of echocardiography data in MHC-Cre vs. KLF15-cKO under fed vs. 48 hour fasting conditions.
Fig 3.
Cardiac specific deletion of KLF15 alters tissue and plasma levels of free fatty acids and triglycerides.
Cardiac FFA (A) and TG (B) levels in control (MHC-Cre) vs. KF15-cKO following 48 hours fasting, (n = 5), *P<0.05 vs. Cre Fed, **P<0.05 vs. CKO Fed, # P<0.05 vs. Cre Fast. Plasma FFA (C) and TG (D) levels in control (MHC-Cre) vs. KLF15-cKO following 48 hours fasting, (n = 5), *P<0.05 vs. Cre Fed, **P<0.05 vs. CKO Fed, # P<0.05 vs. Cre Fast.
Fig 4.
Cardiac specific deletion of KLF15 alters lipid profile.
Metabolomic analysis of long chain acylcarnitines in cardiac tissue from control (MHC-Cre) vs. KLF15-cKO with and without 48 hour fast, (n = 5), *P<0.05 by one-way analysis of variance (ANOVA) with the Tukey post hoc test.
Fig 5.
Short-chain diet rescues the KLF15-dependent attenuation of cardiac function in response to fasting.
(A) qPCR analysis of expression of transporter genes in MHC-Cre vs. KLF15-cKO under fed vs. 48 hour fasting conditions. *P<0.05 vs. Cre Fed, **P<0.05 vs. CKO Fed, # P<0.05 vs. Cre Fast. Values normalized to Ppib. (B) Slc25a20 expression (qPCR) in MHC-Cre vs. KLF15-cKO under fed vs. 48 hour fasting conditions. *P<0.05 vs. Cre Fed, **P<0.05 vs. CKO Fed, # P<0.05 vs. Cre Fast. Values normalized to Ppib. (C) Western blot analysis of CACT levels in MHC-Cre vs KLF15-cKO under fed and 48 hour fasting conditions. α-tubulin used as loading control. (D) Quantification of data in C (n = 3 per group). Two-tailed Student's t-test for unpaired data was used. *P<0.05. (E) Left ventricular fractional shortening from echocardiography performed in control (MHC-Cre) vs. KLF15-cKO under fed vs. 48 hours fasting conditions following 10 weeks of short-chain fatty acid diet, (n = 10). (F) Representative echocardiography image from MHC-Cre vs. KLF15-cKO following 48 hours fasting and 10 weeks of short-chain fatty acid diet. (G) Tabular representation of echocardiography data in MHC-Cre vs. KLF15-cKO under fed vs. 48 hour fasting conditions following 10 weeks of short-chain fatty acid diet.
Fig 6.
Short-chain diet rescues the KLF15-dependent accumulation of long chain acylcarnitines in response to fasting.
Metabolomic analysis of long chain acyl-carnitines in cardiac tissue from control (MHC-Cre) vs. KLF15-cKO with and without 48 hour fast, (n = 6) following 10 weeks of short-chain fatty acid diet, *P<0.05 by one-way analysis of variance (ANOVA) with the Tukey post hoc test.
Fig 7.
Schematic representing KLF15 as a regulator of the cardiac adaptive response to fasting.
Table 1.
Change in long chain acylcarnitine profiles after loss of cardiac KLF15 expression.