β Cell-specific deletion of guanylyl cyclase A, the receptor for atrial natriuretic peptide, accelerates obesity-induced glucose intolerance in mice

Abstract

BackgroundThe cardiac hormones atrial (ANP) and B-type natriuretic peptides (BNP) moderate arterial blood pressure and improve energy metabolism as well as insulin sensitivity via their shared cGMP-producing guanylyl cyclase-A (GC-A) receptor. Obesity is associated with impaired NP/GC-A/cGMP signaling, which possibly contributes to the development of type 2 diabetes and its cardiometabolic complications. In vitro, synthetic ANP, via GC-A, stimulates glucose-dependent insulin release from cultured pancreatic islets and β-cell proliferation. However, the relevance for systemic glucose homeostasis in vivo is not known. To dissect whether the endogenous cardiac hormones modulate the secretory function and/or proliferation of β-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in β-cells.MethodsMice with a floxed GC-A gene were bred to Rip-CreTG mice, thereby deleting GC-A selectively in β-cells (β GC-A KO). Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion were monitored in normal diet (ND)- and high-fat diet (HFD)-fed mice. β-cell size and number were measured by immunofluorescence-based islet morphometry.ResultsIn vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from β GC-A KO mice. Concordantly, in vivo, infusion of BNP mildly enhanced baseline plasma insulin levels and glucose-induced insulin secretion in control mice. This effect of exogenous BNP was abolished in β GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in β-cells. Despite this under physiological, ND conditions, fasted and fed insulin levels, glucose-induced insulin secretion, glucose tolerance and β-cell morphology were similar in β GC-A KO mice and control littermates. However, HFD-fed β GC-A KO animals had accelerated glucose intolerance and diminished adaptative β-cell proliferation.ConclusionsOur studies of β GC-A KO mice demonstrate that the cardiac hormones ANP and BNP do not modulate β-cell’s growth and secretory functions under physiological, normal dietary conditions. However, endogenous NP/GC-A signaling improves the initial adaptative response of β-cells to HFD-induced obesity. Impaired β-cell NP/GC-A signaling in obese individuals might contribute to the development of type 2 diabetes.

NPRC deletion attenuates cardiac fibrosis in diabetic mice by activating PKA/PKG and inhibiting TGF-β1/Smad pathways

“…A continuous subcutaneous infusion of saline was conducted in the DM + saline and DM + NPRC −/− groups, respectively, and infusion of ANP (ANP1-28, MCE, USA; 0.5 μg/kg per minute), BNP (BNP1-32, MCE, USA; 0.03 μg/kg per minute), and CNP (CNP1-22, TargetMol, USA; 0.1 μg/kg per minute) was performed in the DM + ANP, DM + BNP, and DM + CNP groups, respectively. The dose of ANP, BNP, and CNP was chosen by referring to previous studies (27,(54)(55)(56)(57)(58). After 28 days of infusion, these mice were euthanized for morphological and pathological detection.…”

Cone photoreceptor phosphodiesterase PDE6H inhibition regulates cancer cell growth and metabolism, replicating the dark retina response

“…Sildenafil treatment alleviates insulin resistance [ 130 ]. Treatment with ANP-induced cGMP production increases insulin secretion from rat islets, while NO donors and cGMP analogues direct insulin-stimulated GLUT4 translocation and glucose uptake in human vascular smooth muscle cells [ 131 , 132 ]. In mouse cardiomyocytes exposed to pressure overload, sildenafil treatment downregulates genes of Pi3k-Akt pathway, decreases Akt phosphorylation, improves functional mitochondria levels, and lowers ROS while alleviating myopathy [ 133 ].…”

Metabolic Effects of Selective Deletion of Group VIA Phospholipase A2 from Macrophages or Pancreatic Islet Beta-Cells

“…To direct Cre expression in β-cells, RIP-Cre mice were used that express Cre under control of the Rat Insulin 2 Promoter, which has been demonstrated to be appropriate for β-cell-specific gene deletion when used in mice on a pure C57BL/6J background [ 49 ], as is the case in this study, although anomalies may be encountered on other genetic backgrounds [ 53 ]. The use of β-cell-targeting promoters has been reviewed [ 60 ], and the use of RIP-Cre remains a popular means of directing β-cell-restricted gene deletion [ 46 , 50 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. The LysM promoter is expressed in all myeloid cells, and LysM-Cre is widely used to study conditional macrophage-myeloid cell gene deletions [ 52 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ].…”