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

Abstract

SUMMARY We leverage the SM/J mouse to understand glycemic control in obesity. High-fat-fed SM/J mice initially develop poor glucose homeostasis relative to controls. Strikingly, their glycemic dysfunction resolves by 30 weeks of age despite persistent obesity. The mice dramatically expand their brown adipose depots as they resolve glycemic dysfunction. This occurs naturally and spontaneously on a high-fat diet, with no temperature or genetic manipulation. Removal of the brown adipose depot impairs insulin sensitivity, indicating that the expanded tissue is functioning as an insulin-stimulated glucose sink. We describe morphological, physiological, and transcriptomic changes that occur during the brown adipose expansion and remission of glycemic dysfunction, and focus on Sfrp1 (secreted frizzled-related protein 1) as a compelling candidate that may underlie this phenomenon. Understanding how the expanded brown adipose contributes to glycemic control in SM/J mice will open the door for innovative therapies aimed at improving metabolic complications in obesity.

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

“…While both groups develop hyperinsulinemia, diabetic‐obese individuals become insulin resistant, leading to β‐cell dysfunction, hypoinsulinemia, and hyperglycemia. Our previous work shows that obese SM/J mice spontaneously transition from hyperglycemic to normoglycemic with age (Carson et al., 2019). Principle to this is a 40 mg/dl decrease in fasting glucose levels in high fat‐fed SM/J mice between 20 and 30 weeks (Figure 1a).…”

“…Experimental animals were generated at the Washington University School of Medicine and all experiments were approved by the Institutional Animal Care and Use Committee in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals. Mice were weaned onto a high fat diet (42% kcal from fat; Envigo Teklad TD88137) or an isocaloric low fat diet (15% kcal from fat; Research Diets D12284), as previously described (Carson et al., 2019). At 20 or 30 weeks of age, mice were fasted for 4 hr, and blood glucose was measured via glucometer (GLUCOCARD).…”

“…After 20 weeks on a high fat diet, SM/J mice display characteristics of diabetic‐obese mice, including elevated adiposity, hyperglycemia, and glucose intolerance (Ehrich et al., 2003). We have previously shown that by 30 weeks of age, high fat‐fed SM/J mice enter diabetic remission, characterized by normalized fasting blood glucose, and greatly improved glucose tolerance and insulin sensitivity (Carson et al., 2019). Importantly, these changes occur in the context of sustained obesity.…”

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.…”