1.Effects of Short Term Adiponectin Receptor Agonism on Cardiac Function and Energetics in Diabetic db/db Mice
Aleksandre TARKHNISHVILI ; Christoph KOENTGES ; Katharina PFEIL ; Johannes GOLLMER ; Nikole J BYRNE ; Ivan VOSKO ; Julia LUEG ; Laura VOGELBACHER ; Stephan BIRKLE ; Sibai TANG ; Timothy Bon-Nawul MWINYELLA ; Michael M HOFFMANN ; Katja E ODENING ; Nathaly Anto MICHEL ; Dennis WOLF ; Peter STACHON ; Ingo HILGENDORF ; Markus WALLNER ; Senka LJUBOJEVIC-HOLZER ; Dirk von LEWINSKI ; Peter RAINER ; Simon SEDEJ ; Harald SOURIJ ; Christoph BODE ; Andreas ZIRLIK ; Heiko BUGGER
Journal of Lipid and Atherosclerosis 2022;11(2):161-177
Objective:
Impaired cardiac efficiency is a hallmark of diabetic cardiomyopathy in models of type 2 diabetes. Adiponectin receptor 1 (AdipoR1) deficiency impairs cardiac efficiency in non-diabetic mice, suggesting that hypoadiponectinemia in type 2 diabetes may contribute to impaired cardiac efficiency due to compromised AdipoR1 signaling. Thus, we investigated whether targeting cardiac adiponectin receptors may improve cardiac function and energetics, and attenuate diabetic cardiomyopathy in type 2 diabetic mice.
Methods:
A non-selective adiponectin receptor agonist, AdipoRon, and vehicle were injected intraperitoneally into Eight-week-old db/db or C57BLKS/J mice for 10 days. Cardiac morphology and function were evaluated by echocardiography and working heart perfusions.
Results:
Based on echocardiography, AdipoRon treatment did not alter ejection fraction, left ventricular diameters or left ventricular wall thickness in db/db mice compared to vehicle-treated mice. In isolated working hearts, an impairment in cardiac output and efficiency in db/db mice was not improved by AdipoRon. Mitochondrial respiratory capacity, respiration in the presence of oligomycin, and 4-hydroxynonenal levels were similar among all groups. However, AdipoRon induced a marked shift in the substrate oxidation pattern in db/db mice towards increased reliance on glucose utilization. In parallel, the diabetes-associated increase in serum triglyceride levels in vehicle-treated db/db mice was blunted by AdipoRon treatment, while an increase in myocardial triglycerides in vehicle-treated db/db mice was not altered by AdipoRon treatment.
Conclusion
AdipoRon treatment shifts myocardial substrate preference towards increased glucose utilization, likely by decreasing fatty acid delivery to the heart, but was not sufficient to improve cardiac output and efficiency in db/db mice.
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