Obesity and insulinopenic type 2 diabetes differentially impact, bone phenotype, bone marrow adipose tissue, and serum levels of the cathelicidin-related antimicrobial peptide in mice

Abstract

Obesity is a risk factor of developing type 2 diabetes (T2D) and metabolic complications, through systemic inflammation and insulin resistance. It has also been associated with increased bone marrow adipocytes along with increased bone fragility and fracture risk. However, the differential effects of obesity and T2D on bone fragility remain unclear. The cathelicidin-related antimicrobial peptide (CRAMP) is a multifunctional modulator of the innate immunity that has emerged as biomarker of cardiometabolic diseases. The aims of this study were i) to assess the differential impact between hyperinsulinemic obesity versus insulinopenic T2D, on bone phenotype and bone marrow adipose tissue (BMAT), and ii) to analyse the link with CRAMP expression and its circulating levels in the context of obesity and T2D. We used C57BL/6 J male mice models of obesity induced by high-fat diet (HFD), and of insulinopenic T2D induced by streptozotocin (STZ) treatment combined with HFD, reflecting the metabolic heterogeneity of the diseases. As compared to low-fat diet (LFD) control group after 16 weeks of feeding, the HFD mice exhibit a significant weight gain, moderate hyperglycaemia, impaired glucose tolerance and insulin sensitivity, and significant increase in serum insulin levels. This hyperinsulinemic obesity led to decreased trabecular (Tb.Th) and cortical thickness (Ct.Th) in the tibia, associated with significant BMAT expansion, in addition to increased subcutaneaous (SCAT) and visceral adipose tissue (VAT). No changes were observed in the circulating levels of CRAMP peptide neither in other bone parameters. While, STZ treatment in HFD/STZ group induced a more severe hyperglycaemia, glucose intolerance and insulin resistance, and hypoinsulinemia. We also observed a negative effect on the expansion of both SCAT and VAT, as well as lower increase in BMAT as compared to HFD group. However, these mice with insulinopenic T2D exhibit early decrease in trabecular number (Tb.N) in proximal tibia, progressively from 8 to 16 weeks of protocol, and impaired femoral biomechanical stiffness. These alterations are also accompanied with decreased circulating levels of the CRAMP peptide in the HFD/STZ mice. The CRAMP mRNA levels decreased in VAT of both HFD and HFD/STZ groups. Overall, these results provide novel insights into the differential negative impact of obesity versus T2D on bone microenvironment, and suggest a link between hyperglycaemia-induced bone quality alterations during insulinopenia, and impaired regulation of the cathelicidin peptide of the innate immunity. Further investigations are needed to elucidate this relationship.

Keywords: Bone marrow adiposity; Bone microarchitecture; Bone strength; Cathelicidin-related antimicrobial peptide; Diet-induced obesity; Type 2 diabetes.