Multiphasic Regulation of Systemic and Peripheral Organ Metabolic Responses to Cardiac Hypertrophy

Abstract

Background Reduced fat oxidation in hypertrophied hearts coincides with a shift of carnitine palmitoyl transferase I from muscle (CPT1b) to increased liver (CPT1a) isoforms. Acutely increased CPT1a in normal rodent hearts has been shown to recapitulate the reduced fat oxidation and elevated ANP message of cardiac hypertrophy. Methods and Results Due to the potential for reduced fat oxidation to affect cardiac ANP thus induce adipose lipolysis, we studied peripheral and systemic metabolism in male C57BL/6 mice mouse model of transverse aortic constriction (TAC) in which LV hypertrophy occurred by 2 wk without functional decline until 16 wk (EF −45.6%; FS −22.6%). We report the first evidence for initially improved glucose tolerance (GT) and insulin sensitivity (IS) in response to 2 wks TAC vs SHAM, linked to enhanced insulin signaling in liver and visceral adipose tissue (eWAT), reduced white adipose (WAT) inflammation, elevated adiponectin, mulitilocular subcutaneous adipose tissue (iWAT) with upregulated oxidative/thermogenic gene expression, and downregulated lipolysis and lipogenesis genes in eWAT. By 6 wks TAC, the metabolic profile reversed with impaired IS and GT, reduced insulin signaling in liver, eWAT and heart, and downregulation of oxidative enzymes in brown adipose tissue and oxidative and lipogenic genes in iWAT. Conclusions Changes in insulin signaling, circulating natriuretic peptides and adipokines, and varied expression of adipose genes associated with altered insulin response/glucose handling and thermogenesis occurred prior to any functional decline in TAC hearts. The findings demonstrate multiphasic responses in extra-cardiac metabolism to pathogenic cardiac stress, with early iWAT browning providing potential metabolic benefits.

Multiplexed Optical Imaging of Energy Substrates Reveals That Left Ventricular Hypertrophy Is Associated With Brown Adipose Tissue Activation

“…However, downstream to these receptors, only fatty acid transporter 1 (FATP1) mRNA was increased (1.8×) in banded mice (p = 0.006; Figure 2E) whereas the mRNA levels for several of the remaining key enzymes involved in FFA and glucose handling were not different (all p>0.05) in BAT from control vs banded animals, including: carnitine palmitoyltransferase 1b (CPT1B), medium-chain acyl-CoA dehydrogenase (MCAD), glucose transporter 1 (GLUT1), glucose transporter 4 (GLUT4) and pyruvate dehydrogenase kinase 4 (PDK4) (Panels 2E and F). A non-significant decrease in UCP1 mRNA was seen at 5 weeks (data not shown), in agreement with a recent report 24 . However, UCP1 protein abundance was unchanged in banded animals (Figure 2D) (p = 0.62).…”

“…Despite no sign of decompensation at the 5-week time point, an increase in the upstream receptors responsible for BAT activation (increased β 3 AR and increased NPRa/c ratio) was seen, suggesting that BAT signaling was affected by TAC physiology. In a recent report, changes in β 3 AR mRNA in BAT were not observed 6 weeks post TAC 24 , however differences in gender and technique may account for this difference. Increases in β 3 AR as well as the NPRa/c ratio have been shown to occur in ‘beiging’ of WAT 33,34 , and our data suggest that a similar phenomenon may occur early in the process of chronic BAT activation associated with LVH.…”

A peptide of the amino-terminus of GRK2 induces hypertrophy and yet elicits cardioprotection after pressure overload

“…Physiological hypertrophy is marked not only by an increase in cell survival signaling, but also increased and efficient energy production, antioxidant regulation, and enhanced mitochondrial quality control that antagonize pathological remodeling to produce a purely adaptive response. Further, not only changes in cardiomyocyte, but systemic metabolism, precede heart failure development [58][59][60][61][62]. While elevated cardiac levels and activity of GRK2 contribute to adverse heart remodeling and contractile dysfunction, inhibition of GRK2 via overexpression of a carboxyl-terminal peptide, βARKct, or its amino-terminal RGS homology domain (βARKrgs) can enhance cardiac function and can prevent heart failure development via G βγ or Gαq sequestration, respectively [1,[4][5][6].…”

Enhancing natriuretic peptide signaling in adipose tissue, but not in muscle, protects against diet-induced obesity and insulin resistance

“…NPRA activation also leads to uncoupled respiration in brown adipocytes and increases browning of WAT, again in a parallel pathway to the βARs ( 41 ). Because a growing body of evidence places the NP system at the center of “cardiometabolic” disease ( 42 ), including the adipocyte response to early pathological stress on the heart ( 43 ), we studied their tissue-specific effects by manipulating NPRC abundance.…”