Spontaneous restoration of functional β-cell mass in obese SM/J mice

Abstract

48Maintenance of functional β-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause 49 β-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously 50 transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-51 cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and β-cell function during SM/J's 52 diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and 53 pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that 54 obese SM/J mice selectively increase β-cell mass but not α-cell mass. Obese SM/J mice do not show elevated β-55 cell mitotic index, but rather elevated α-cell mitotic index. Functional assessment of isolated islets reveals that obese 56 SM/J mice increase glucose stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin 57 content. These results establish that β-cell mass expansion and improved β-cell function underlie the resolution of 58 hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional β-cell mass can 59 be recovered in the context of obesity. 60 61 62 63 64 65 66 67 68 69 70 71 72

Brown Adipose Expansion and Remission of Glycemic Dysfunction in Obese SM/J Mice

“…By 30 weeks, despite the persistence of obesity, high-fat-fed SM/J mice resolve their hyperglycemia and impaired glucose tolerance to levels indistinguishable from low-fat-fed controls ( Figures 1A – 1D ). Thirty-week high-fat-fed SM/J mice have dramatically increased serum and pancreatic insulin levels compared with 20-week animals ( Miranda et al, 2020 ), and insulin sensitivity improves along with improved glycemic parameters ( Figures 1E and 1F ). Notably, metabolic hormones, such as adiponectin, glucagon, IGF1, and leptin, do not show any changes in circulating levels between 20 and 30 weeks ( Figures S1A – S1D ).…”

“…To test these predictions, we removed the interscapular brown adipose depots from hyperglycemic 20-week-old and normoglycemic 30-week-old mice. Interestingly, removal of the brown adipose depot at 20 weeks does not affect serum glucose or insulin levels, or the glucose tolerance of the animals, indicating that the expanded brown adipose is downstream of the primary signal ( Figures 2F – 2H ) ( Miranda et al, 2020 ). However, removal of the brown adipose depot before expansion prevents the natural improvement in insulin tolerance, and removal of the expanded tissue at 30 weeks results in a reversion to 20-week-old measurements ( Figure 2I ).…”

Integrated transcriptomics identifies β-cell subpopulations and genetic networks associated with obesity and glycemic control in SM/J mice

“…The copyright holder for this preprint (which this version posted July 15, 2021. ; https://doi.org/10.1101/2021.07.15.452524 doi: bioRxiv preprint 21 high-fat males 20,21 . Several groups have identified a subset of heavily vascularized islets that have elevated oxygen consumption and superior GSIS at the cost of susceptibility to hypoxia.…”

“…In conjunction, hyperglycemic obese mice express a highly connected genetic network associated with fatty acid metabolism, which is lost as glycemic control improves. The interplay between changing β-cell subpopulations and decreased fatty acid metabolism likely contributes to the improved β-cell function and subsequent restoration of glycemic control seen in obese SM/J mice 20,21 . This study provides a road map for exploring cellular heterogeneity by integrating sc-and bulk RNA-seq data, allowing for robust characterization of subpopulation structure, differential expression, and network analysis associated with obesity and glycemic stress.…”

“…15.452524 doi: bioRxiv preprint Islet isolation and phenotyping. Islets were isolated from pancreas as previously described 20 and rested overnight.…”