The cardiac METTL3/m6A pathway regulates the systemic response to Western diet
Charles Rabolli, Jacob Z. Longenecker, Isabel S. Naarmann-de Vries, Joan Serrano, Jennifer M. Petrosino, George A. Kyriazis, Christoph Dieterich, Federica Accornero
Charles Rabolli, Jacob Z. Longenecker, Isabel S. Naarmann-de Vries, Joan Serrano, Jennifer M. Petrosino, George A. Kyriazis, Christoph Dieterich, Federica Accornero
View: Text | PDF
Research Article Cardiology Muscle biology

The cardiac METTL3/m6A pathway regulates the systemic response to Western diet

Abstract

Regulation of organismal homeostasis in response to nutrient availability is a vital physiological process that involves interorgan communication. The role of the heart in controlling systemic metabolic health is not clear. Adopting a mouse model of diet-induced obesity, we found that the landscape of N6-methyladenosine (m6A) on cardiac mRNA was altered following high-fat/high-carbohydrate feeding (Western diet). m6A is a critical posttranscriptional regulator of gene expression, the formation of which is catalyzed by methyltransferase-like 3 (METTL3). Through parallel unbiased approaches of Nanopore sequencing, mass spectrometry, and protein array, we found regulation of circulating factors under the control of METTL3. Mice with cardiomyocyte-specific deletion of METTL3 showed a systemic inability to respond to nutritional challenge, thereby mitigating the detrimental effects of Western diet. Conversely, increasing cardiac METTL3 level exacerbated diet-induced body weight gain, adiposity, and glucose intolerance. Our findings position the heart at the center of systemic metabolism regulation and highlight an m6A-dependent pathway to be exploited for the battle against obesity.

Authors

Charles Rabolli, Jacob Z. Longenecker, Isabel S. Naarmann-de Vries, Joan Serrano, Jennifer M. Petrosino, George A. Kyriazis, Christoph Dieterich, Federica Accornero

×

Figure 2

Cardiac M3KO mice have unchanged cardiac structure and function.

Options: View larger image (or click on image) Download as PowerPoint
Cardiac M3KO mice have unchanged cardiac structure and function. (A) Sch...
(A) Schematic overview of the creation of METTL3 cardiomyocyte-specific knockout (M3KO). (B–D) Body weight and subcutaneous and visceral white adipose tissue (WAT) of control and M3KO mice at 6 and 12 months of age. n = (10; 6; 26; 17/18) (Ctrl 6 mo.; M3KO 6 mo.; Ctrl 12 mo.; M3KO 12 mo.). (E and F) Percentage increase of weekly body weights of female and male mice for 12 weeks following control or Western diet in control or M3KO animals. n (females) = (6; 8; 5; 8) and n (males) = (4; 3; 6; 6) (CD Ctrl; CD M3KO; WD Ctrl; WD M3KO). (G and H) Representative Masson’s trichrome–stained cardiac cross sections from the indicated groups and fibrosis quantification. n = (4; 8; 4; 7) (CD Ctrl; CD M3KO; WD Ctrl; WD M3KO). (I and J) Cardiomyocyte cross-sectional area determined by wheat germ agglutinin (WGA) staining. Scale bar = 125 μm. n = (5; 8; 4; 8) (CD Ctrl; CD M3KO; WD Ctrl; WD M3KO). (K) Heart weight normalized to tibia length after 12 weeks on control diet or Western diet. n = (10; 11; 9; 14) (CD Ctrl; CD M3KO; WD Ctrl; WD M3KO). (L) Cardiac ejection fraction measured via echocardiography after 12 weeks of diet. n = (10; 11; 10; 14) (CD Ctrl; CD M3KO; WD Ctrl; WD M3KO). (M and N) Metabolic treadmill test for maximal oxygen consumption (VO2 max) and running time until exhaustion determined via a graded exercise protocol. n = (9; 11; 9/10; 14) (CD Ctrl; CD M3KO; WD Ctrl; WD M3KO). Data shown as mean ± SEM. Two-way ANOVA with multiple comparisons test were used (B–F and H–N); *P < 0.05, **P < 0.01, ****P < 0.0001. βMHC, β–myosin heavy chain.