Acute and Chronic Increases of Circulating FSTL1 Normalize Energy Substrate Metabolism in Pacing-Induced Heart Failure

Abstract

These findings support a novel function for FSTL1 and provide the first direct evidence that a circulating cardiokine/myokine can alter myocardial and systemic energy substrate metabolism, in vivo.

The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense

“…The infusion of 3OHB did not significantly alter the arterial levels of free fatty acid (FFA) and glucose, while it caused a slight, albeit significant, reduction in circulating lactate (Supplemental Figure 5A). Consistent with previous studies in this model (22), palmitate oxidation rates decreased and glucose oxidation rates increased in the HF group compared with controls in the absence of 3OHB treatment ( Figure 5, B and C). In the failing heart, myocardial glucose uptake and oxidation rates were markedly suppressed by 3OHB infusion, whereas FFA uptake and oxidation was not significantly changed ( Figure 5, B-E).…”

“…Recently, we and others found that the hypertrophied and failing mouse heart utilizes ketone bodies at increased rates (20,21). These results, together with observations that circulating ketone bodies are increased in humans and experimental dogs with HF (22,38,39), suggest that the failing heart oxidizes ketone bodies as an ancillary fuel in the context of reduced capacity to burn fatty acids, the chief substrate of the normal heart. However, the role of chronic ketone utilization as adaptive or maladaptive in the failing heart is unknown.…”

“…BDH1 is a mitochondrial enzyme that catalyzes the first step in the oxidation of 3-hydroxybutyrate (3OHB), a ketone body that is synthesized mainly in the liver. 13 C-NMR spectroscopy studies confirmed that the hypertrophied mouse heart utilizes 3OHB to a greater extent than the normal heart (20), and in vivo measurements confirmed a higher ketone body uptake by canine failing hearts (22). Taken together, the results of these recent studies suggest that, in the context of reduced capacity to oxidize fatty acids as a fuel, the heart reprograms to increase utilization of ketone bodies generated in the liver.…”

“…Surgical instrumentation. Thirteen male mongrel dogs (aged 9-12 months; 21-27 kg) were chronically instrumented with a solid state pressure gauge inserted in the left ventricle, 3 fluid-filled catheters (1 inserted in the descending thoracic aorta, 1 in the right ventricle, and 1 in the left atrium), a Doppler flow probe placed around the left circumflex coronary artery, and 2 pacing leads attached to the LV epicardial surface, as previously described (22,30). The dogs wore cotton/nylon jackets to protect the exteriorized wires and catheters.…”

High circulating follistatin-like protein 1 as a biomarker of a metabolically unhealthy state

“…Follistatin-like protein 1 (FSTL1) contains 308 amino acids and is an extracellular glycoprotein that is mainly produced by cells with a mesenchymal origin [15]. Recent studies have suggested that FSTL1 could be a biomarker of inflammation [15,16] and CVD [17][18][19]. These findings suggest that FSTL1 can serve as an inflammatory biomarker for differentiating metabolically healthy (MH) and MU state in order to predict CVD risk.…”