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

Abstract

Maintenance of functional β‐cell mass is critical to preventing diabetes, but the physiological mechanisms that cause β‐cell populations to thrive or fail in the context of obesity are unknown. High fat‐fed SM/J mice spontaneously transition from hyperglycemic‐obese to normoglycemic‐obese with age, providing a unique opportunity to study β‐cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and β‐cell function during SM/J’s diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase β‐cell mass but not α‐cell mass. Obese SM/J mice do not show elevated β‐cell mitotic index, but rather elevated α‐cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose‐stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that β‐cell mass expansion and improved β‐cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional β‐cell mass can be recovered in the context of obesity.

Parent-of-origin effects propagate through networks to shape metabolic traits

“…We generated mRNA expression profiles in white adipose tissue from 20-week-old F1 reciprocal cross animals. These animals were subjected to the same high and low-fat diets and phenotyping protocols as the previously studied F16 animals (Cheverud et al 2011;Lawson et al 2011aLawson et al , 2010Carson et al 2020;Miranda et al 2020). We identified two classes of genes: 1) imprinted genes, and 2) non-imprinted genes with parent-of-origin effects on total expression.…”

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

“…Further, 20wk high-fat males have similar islet mass to 30wk high-fat males, but a much smaller Beta 2 population. Importantly, 30wk high-fat males have healthier glycemic parameters than 20wk 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.…”

“…We identify subtype-specific expression of Pdyn and Fam151a as candidate regulators of genetic pathways associated with β-cell function in obesity. In sum, this study uses a novel data integration method to explore how β-cells respond to obesity and glycemic stress, helping to define the relationship between β-cell heterogeneity and diabetes, and shedding light on novel genetic pathways with therapeutic potential.Here, we characterize gene expression in β-cells from obese SM/J mice, who spontaneously transition from hyperglycemic to normoglycemic with improved β-cell function between 20 and 30 weeks of age 20,21 . We assign functional identities to 4 subpopulations of β-cells using scRNA-seq.…”

“…Here, we characterize gene expression in β-cells from obese SM/J mice, who spontaneously transition from hyperglycemic to normoglycemic with improved β-cell function between 20 and 30 weeks of age 20,21 . We assign functional identities to 4 subpopulations of β-cells using scRNA-seq.…”