Insulin/glucose induces natriuretic peptide clearance receptor in human adipocytes: a metabolic link with the cardiac natriuretic pathway

Abstract

Cardiac natriuretic peptides (NP) are involved in cardiorenal regulation and in lipolysis. The NP activity is largely dependent on the ratio between the signaling receptor NPRA and the clearance receptor NPRC. Lipolysis increases when NPRC is reduced by starving or very-low-calorie diet. On the contrary, insulin is an antilipolytic hormone that increases sodium retention, suggesting a possible functional link with NP. We examined the insulin-mediated regulation of NP receptors in differentiated human adipocytes and tested the association of NP receptor expression in visceral adipose tissue (VAT) with metabolic profiles of patients undergoing renal surgery. Differentiated human adipocytes from VAT and Simpson-Golabi-Behmel Syndrome (SGBS) adipocyte cell line were treated with insulin in the presence of high-glucose or low-glucose media to study NP receptors and insulin/glucose-regulated pathways. Fasting blood samples and VAT samples were taken from patients on the day of renal surgery. We observed a potent insulin-mediated and glucose-dependent upregulation of NPRC, through the phosphatidylinositol 3-kinase pathway, associated with lower lipolysis in differentiated adipocytes. No effect was observed on NPRA. Low-glucose medium, used to simulate in vivo starving conditions, hampered the insulin effect on NPRC through modulation of insulin/glucose-regulated pathways, allowing atrial natriuretic peptide to induce lipolysis and thermogenic genes. An expression ratio in favor of NPRC in adipose tissue was associated with higher fasting insulinemia, HOMA-IR, and atherogenic lipid levels. Insulin/glucose-dependent NPRC induction in adipocytes might be a key factor linking hyperinsulinemia, metabolic syndrome, and higher blood pressure by reducing NP effects on adipocytes.

Natriuretic peptides in the control of lipid metabolism and insulin sensitivity

“…However, insulin might attenuate ANP‐mediated lipolysis by inducing NPRC expression, as described earlier in this review. Of interest, the presence of low‐glucose conditions together with insulin stimulation abolished NPRC expression to basal levels, indicating the existence of a ‘nutritional signalling’ in NPRC regulation . The relative ratio of NPRA to NPRC mRNA levels in subcutaneous AT was decreased depending on glucometabolic status because patients with T2DM had the lowest ratio compared with subjects with normal glucose tolerance or impaired glucose metabolism .…”

“…Additionally, it has been shown that NPRC mRNA expression is down‐regulated in vitro following starvation in human differentiated adipocytes and in vivo in rat white and BAT while the opposite was true under high‐fat feeding in wild‐type mice skeletal muscle and white and BAT . Like NPRC, NEP expression is increased in the plasma (protein) and AT (mRNA) of obese subjects, although there is no direct evidence for an increased NEP activity in human obesity .…”

Critical role of the epicardium in mediating cardiac inflammation and fibrosis in patients with type 2 diabetes

“…Increased levels of aldosterone precede and predict the development of type 2 diabetes, and spironolactone ameliorates insulin resistance . Conversely, the development of diabetes is accompanied by decreased circulating levels of and impaired adipocyte responsiveness to natriuretic peptides . It is therefore noteworthy that mineralocorticoid receptor signalling is required for the differentiation of adipocytes and their transition to a proinflammatory biology, whereas natriuretic peptides act in a counterregulatory manner to limit adipogenesis and restrain the proinflammatory transformation of adipose tissue (Figure ) .…”

Cardiac Natriuretic Peptides, Hypertension and Cardiovascular Risk

“…Two main antagonistic circulating regulatory systems may be associated with these conditions: cardiac NPs and renin angiotensin aldosterone system (RAAS). The head-to-head between NPs and RAAS appears of key value to understand the pathophysiology of obesity-related complications such as hypertension, insulin resistance and MetS [7, 32]. …”

“…A recent study have confirmed that high insulin levels, together with high glucose concentration (as in impaired glucose tolerance of MetS), induced NPRC overexpression in human adipocytes, blocking NP-mediated lipolysis and thermogenic pathway, and potentially contributing to lower energy dissipation, increase adiposity, insulin resistance and BP. In contrast, when insulin was not coupled with high glucose concentration, simulating fasting condition and suggesting a “nutritional signaling”, NPRC gene expression was not induced [32]. It is possible to speculate that the strong lipolytic effects of NPs are counterbalanced by insulin and insulin-mediated NPRC induction.…”