Kruppel-like factor 15 is required for the cardiac adaptive response to fasting.

Cardiac metabolism is highly adaptive in response to changes in substrate availability, as occur during fasting. This metabolic flexibility is essential to the maintenance of contractile function and is under the control of a group of select transcriptional regulators, notably the nuclear receptor family of factors member PPARα. However, the diversity of physiologic and pathologic states through which the heart must sustain function suggests the possible existence of additional transcriptional regulators that play a role in matching cardiac metabolism to energetic demand. Here we show that cardiac KLF15 is required for the normal cardiac response to fasting. Specifically, we find that cardiac function is impaired upon fasting in systemic and cardiac specific Klf15-null mice. Further, cardiac specific Klf15-null mice display a fasting-dependent accumulation of long chain acylcarnitine species along with a decrease in expression of the carnitine translocase Slc25a20. Treatment with a diet high in short chain fatty acids relieves the KLF15-dependent long chain acylcarnitine accumulation and impaired cardiac function in response to fasting. Our observations establish KLF15 as a critical mediator of the cardiac adaptive response to fasting through its regulation of myocardial lipid utilization

Short-chain diet rescues the KLF15-dependent attenuation of cardiac function in response to fasting.

<p>(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 <i>Ppib</i>. (B) <i>Slc25a20</i> 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 <i>Ppib</i>. (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 <i>t</i>-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.</p

Cardiac specific deletion of KLF15 alters lipid profile.

<p>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.</p

Cardiac specific deletion of KLF15 alters tissue and plasma levels of free fatty acids and triglycerides.

<p>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.</p

Cardiac KLF15 is required for the heart’s functional adaptation in response to fasting.

<p>(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.</p

Change in long chain acylcarnitine profiles after loss of cardiac KLF15 expression.

<p>Change in long chain acylcarnitine profiles after loss of cardiac KLF15 expression.</p

Systemic KLF15 is required for the heart’s functional adaptation in response to fasting.

<p>(A) Left ventricular fractional shortening from echocardiography performed in wild-type (WT) vs. systemic <i>Klf15</i>-null (<i>Klf15-/-</i>) under fed vs. 48 hours fasting conditions, (n = 5), *P,0.05 vs. WT Fast. (B) Representative echocardiography image from WT vs. <i>Klf15-/-</i> following a 48 hour fast. (C) Tabular representation of echocardiography data in WT vs. <i>Klf15-/-</i> under fed vs. 48 hour fasting conditions.</p