Tschoep, M. | Search bioRxiv

bioRxiv2022

GIP receptor agonism improves dyslipidemia and atherosclerosis independently of body weight in obese mice

Agonism at the receptors for the glucose-dependent insulinotropic polypeptide (GIPR) is a key component of the novel unimolecular co-agonists which are among the most promising drugs in clinical development for the treatment of obesity and diabetes. The therapeutic effect of chronic GIPR agonism to treat dyslipidemia, and thus to reduce the cardiovascular disease risk, has not been explored yet. Herein we found that treatment with a long-acting acylated GIP analog (Acyl-GIP) reduced dyslipidemia and atherogenesis in male LDL receptor knockout mice. Acyl-GIP administration resulted in smaller adipocytes within the inguinal fat depot and RNAseq analysis of the latter revealed that Acyl-GIP may improve dyslipidemia by directly modulating lipid metabolism in this fat depot. This study identified an unanticipated efficacy of chronic GIPR agonist administration to improve dyslipidemia and cardiovascular disease.

pharmacology and toxicology↗

bioRxiv2022

Adipose cells and tissues soften with lipid accumulation while in diabetes adipose tissue stiffens

Adipose tissue expansion involves both differentiation of new precursors and size increase of mature adipocytes. While the two processes are well balanced in healthy tissues, obesity and diabetes type II are associated with abnormally enlarged adipocytes and excess lipid accumulation. We hypothesised that adipocyte shape and size changes with differentiation and lipid accumulation would be accompanied by changes in the mechanical phenotype at both the cell and tissue level. We quantified by optical diffraction tomography (ODT) that differentiating preadipocytes increased their volumes drastically. Atomic force microscopy (AFM)-indentation and -microrheology revealed that during the early phase of differentiation, human preadipocytes became more compliant and more fluid-like, concomitant with ROCK-mediated F-actin remodelling. Adipocytes that had accumulated large lipid droplets were more compliant, and further promoting lipid accumulation led to an even more compliant phenotype. In line with that, high fat diet-induced obesity was associated with more compliant adipose tissue compared to lean animals, both for drosophila fat bodies and murine gonadal adipose tissue. In contrast, adipose tissue of diabetic mice became significantly stiffer as shown not only by AFM but also magnetic resonance elastography (MRE). Altogether, we dissect relative contributions of the cytoskeleton and lipid droplets to cell and tissue mechanical changes across different functional states, such as differentiation, nutritional state and disease. Since preadipocytes are mechanosensitive, tissue stiffening in diabetes might be critical to the balance between hyperplasia and hypertrophy and moreover present a potential target in the prevention of metabolic disorders.

biophysics↗