Loss of visceral adipose tissue resident macrophages in heart failure-induced insulin resistance: Role of adiponectin

Project: Research


  • Sathish Babu Babu Vasamsetti (PI)


Heart failure is a major cause of morbidity and mortality in the modern world. Laboratory and clinical studies document strong associations between insulin resistance and heart failure. Insulin resistance has a direct detrimental effect on ischemic myocardium and inflates the incidence of secondary myocardial infarction (MI). Hence, understanding the predisposing mechanisms of insulin resistance in heart failure is essential for the treatment.Visceral adipose tissue (VAT) inflammation drives local dysfunction as well as systemic pathogenic consequences, such as insulin resistance. Besides regulating fat mass and nutrient homeostasis, VAT acts as an active endocrine organ. It secretes a large number of bioactive mediators called 'adipocytokines' into the systemic circulation, that signal to organs of metabolic importance like liver, skeletal muscle thereby modulating lipid and glucose metabolism. Pro-inflammatory adipocytokines like leptin, IL-6 contribute to metabolic complications like insulin resistance. Anti-inflammatory adipocytokines like adiponectin, vaspin with insulin sensitizing effects on liver and muscle promote the glucose uptake efficiently and prevent insulin resistance. Impaired homeostasis of VAT myeloid cells, particularly macrophages (macs) are key regulators of insulin sensitivity or resistance. Based on their origins, tissue macs are a. tissue resident and b. blood monocyte derived. The role of VAT resident macs is poorly understood due to lack of proper cell surface markers to identify this mac subset. Based on chemokine receptors- CX3CR1 and CCR2 expression, we discovered 2 main subsets of macs in VAT: 1) CX3CR1+ CCR2+ and 2) CX3CR1-CCR2-. Using parabiosis and lineage tracing studies, we found that CX3CR1+ CCR2+ macs are blood monocyte-derived, whereas CX3CR1- CCR2- macs are resident. RNA sequencing analysis revealed that CX3CR1-CCR2- macs express insulin sensitivity promoting genes highlighting a potential role of these macs in maintaining insulin sensitivity. Using samples from patients with acute myocardial injury and mouse models of MI-induced HF, we observed that the number of VAT resident macs significantly reduced due to apoptosis. This loss of VAT resident macs after MI was accompanied by systemic insulin resistance in non-diabetic patients and mice. Furthermore, we observed that the level of adiponectin, which is reported to augment insulin sensitivity, was profoundly reduced in serum of mice with heart failure.
Award amount$139,336.00
Award date01/01/2020
Program typePostdoctoral Fellowship
Award ID20POST35210088
Effective start/end date01/01/202012/31/2021