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Background Glucose-dependent insulinotropic peptide (GIP) is incretin hormone that is emerged as an important regulator of lipid metabolism. Fat intake induces hypersecretion of GIP that is involved in obesity and ectopic fat accumulation. Aging is another stimulant of GIP hypersecretion, which is suggested as a cause of “sarcopenic obesity in elderly”. In heart, aging is the known risk factor of HFpEF, of which typical characteristics is pathological cardiac hypertrophy induced by unknown cause(s). It remained uncertain whether any ectopic fat accumulation, such as cardiac steatosis may cause the aging-induced cardiac hypertrophy. Ceramide is one of the lipid metabolites that involves in apoptosis, inflammation, and stress responses, which are among the pathogenic components of heart failure. However, it remained unclear whether the ceramide may play any pathophysiological role in cardiac aging. Purpose We thus hypothesized whether cardiac aging may alter cardiac lipid metabolism and the GIP may play a regulatory role in the cardiac aging via modulating cardiac steatosis, particularly ceramide. Methods Mouse model of GIPR deficiency (GIPR-KO) was employed and cardiac evaluation of GIPR-KO and the age-matched wild type mice were performed. Results Aging (50w/o) induced GIP hypersecretion in control mice and their body and heart weight were 50% increased as compared to younger counterpart (10w/o). In contrast, the aging-induced increase rate in body and heart weight of GIPR-KO was significantly lower (22%). Aging also increased the circulating ketone bodies with increase in FGF21 expression in heart and, notably, there was no pathological increase in cardiac ceremide and oxidative stress with normal left-ventricular (LV) function (LVEF=82.2±1.8). In contrast, GIPR-KO exhibited pathological increase in cardiac ceramide without the elevation of the circulating ketone bodies. The younger GIPR-KO (10 w/o) exhibited normal left-ventricular (LV) function, however, the older mice (50 w/o) exhibited systolic LV dysfunction (LVEF=55.8±8.5) with increase in cardiac apoptosis and oxidative stress. Cardiac ceramide accumulation was increased in the aged normal mice, which was significantly higher in the aged GIPR-KO. Furthermore, GIPR-KO exhibited increase in cardiac fibrosis and oxidative stress, which were absent in the aged normal counterpart. Conclusion Aging increased circulating GIP level the leads to compensatory rise in the circulating ketone bodies without pathological increase in cardiac ceremide and related oxidative stress in heart. Loss of GIP signaling caused pathological increase in cardiac ceramide, leading to the aging-induced progression of systolic left-ventricular dysfunction. Collectively, we conclude that the aging-induced GIP hyperexcretion is essential for the aging-induced healthy cardiac remodeling by augmenting compensatory ketone body elevation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): KAKEN-HI

Background/Introduction Incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are secreted from the small intestine and emerged as important participants in glucose homeostasis that involves in the pathogenesis of type 2 diabetes (T2D). stimulate glucose-dependent insulin biosynthesis. Emerging data suggest important extrapancreatic functions for GLP-1 on cardiovascular system. However, limited evidence has been emerged whether GIP may play any pathophysiological role in heart. GIP promotes insulin secretion leading to augment insulin-induced lipogenesis. Recent research has highlighted the relevance of the GIP/GIPR axis in principal insulin-sensitive organs such as adipose tissue. Heart is another insulin-sensitive organ in which insulin promotes hypertrophy of myocardium presumably via activation of Akt pathway. In T2DM, ectopic accumulation of lipid and fat to myocardium that is known as “cardiac steatosis”; however, it remains uncertain whether the GIP/insulin axis may modulate cardiac steatosis observed in T2DM. Purpose To elucidate that physiological GIP may play a regulatory role in cardiac pathophysiology. Methods We employed mouse model of GIPR deficiency (GIPR-KO) that was generated by lacking the GIPR gene (GIPR), by replacing exons 4 and 5 of GIPR with the PGK-neo cassette. Cardiac evaluation of GIPR-KO was performed at the age of 6 week-old (w/o), 10 w/o, 23 w/o, and 53 w/o. Results GIPR deficient mice (GIPR-KO) exhibited normoglycemia, but their circulating free acid level and ketone level were elevated. Interestingly, GIPR-KO at younger age (6-week-old and 10-week old) exhibited normal left-ventricular (LV) function, however, older mice aged older than 20-week-old exhibited significant systolic left-ventricular dysfunction (FS (%) 55.2±1.9 for Wild-type, 32.1±2.6 for 23-w/o-GIPR-KO, 28.5±2.6 for 56-w/o-GIPR-KO, P<0.01). Histological analysis revealed that cardiomyocyte size was decreased and capillary density was increased in GIPR-KO. Interestingly, TUNEL staining revealed that there was no increase in cardiac apoptosis in GIPR-KO. In contrast, GIPR-KO exhibited increase in cardiac fibrosis (Picro-sirius staining) and oxidative stress (DHE staining). Myocardial triglyceride accumulation was decreased in GIPR-KO heart. QPCR analysis revealed GIPR-KO heart exhibited increase in BNP level and decline in fibroblast growth factor 21 (FGF-21), an hormonal activator for energy expenditure in adipocyte. GIP augmented FGF-21 expression in cardiomyocytes via PPARalfa. Conclusion Loss of GIP signaling caused impaired fatty acid metabolism in heart via impairment of FGF21 pathway and oxidative stress, leading to an age-dependent progression of cardiac dysfunction.