Brown adipose expansion and remission of glycemic dysfunction in obese SM/J mice

Abstract

52Disruption of glucose homeostasis increases the risk of type II diabetes, cardiovascular disease, stroke, 53 and cancer. We leverage a novel rodent model, the SM/J mouse, to understand glycemic control in 54 obesity. On a high fat diet, obese SM/J mice initially develop impaired glucose tolerance and elevated 55 fasting glucose. Strikingly, their glycemic dysfunction resolves by 30 weeks of age despite persistence of 56 obesity. A prominent phenotype is that they dramatically expand their brown adipose depots as they 57 resolve glycemic dysfunction. This occurs naturally and spontaneously on a high fat diet, with no 58 temperature or genetic manipulation. When the brown adipose depot is removed from normoglycemic 59 obese mice, fasting blood glucose and glucose tolerance revert to unhealthy levels, and animals become 60 insulin resistant. We identified 267 genes whose expression changes in the brown adipose when the 61 mice resolve their unhealthy glycemic parameters, and find the expanded tissue has a 'healthier' 62 expression profile of cytokines and extracellular matrix genes. We describe morphological, physiological, 63 and transcriptomic changes that occur during the unique brown adipose expansion and remission of 64 glycemic dysfunction in obese SM/J mice. Understanding this phenomenon in mice will open the door for 65 innovative therapies aimed at improving glycemic control in obesity.66 67 Significance Statement 68 Some obese individuals maintain normal glycemic control. Despite being obese, these individuals 69 have low risk for metabolic complications, including type-II diabetes. If we better understood why some 70 obese people maintain normoglycemia then we might develop new approaches for treating metabolic 71 complications associated with obesity. However, the causative factors underlying glycemic control in 72 obesity remain unknown. We discovered that, despite persistence of the obese state, SM/J mice enter 73 into diabetic remission: returning to normoglycemia and reestablishing glucose tolerance and improving 74 insulin sensitivity. A prominent phenotype is that they dramatically expand their brown adipose depots as 75 they resolve glycemic dysfunction. Understanding this phenomenon in mice will open the door for 76 innovative therapies aimed at improving glycemic control in obesity. 78An estimated 10-30% of obese individuals maintain glycemic control and some longitudinal 79 studies suggest their risk of developing type II diabetes is no greater than matched lean individuals (1). 80No causative factors underlying glycemic control in obesity have been discovered, however the strongest 81 predictors of impaired glycemic control in obesity are increased visceral fat mass and adipose tissue 82 dysfunction (2,3). Thus research efforts have focused on understanding the genetic and physiological 83 mechanisms of action of adipose. Recent research reveals that brown adipose activity is associated with 84 anti-diabetic properties. Cold exposure in both obese and lean individuals causes increased uptake...

Genetic background and diet affect brown adipose gene co-expression – metabolic associations

“…This is consistent with our previous work showing brown adipose tissue-dependent resolution of diabetes in high fat-fed SM/J mice [51]. Twenty-four of these hub genes contain small nucleotide variants between the LG/J and SM/J strains [57] ( Supplementary Table 6 ), which could be contributing to the gene-by-environmental differential expression patterns we observe.…”

“…The brown cell division module shows remarkable clustering of the high fat-fed SM/J cohort, which is consistent with our result that enrichment of this term is driven by high fat-fed SM/J mice. Further, high fat-fed SM/J mice have the highest brown adipose to body weight ratios and our previous work showed that the brown adipose expansion observed in these mice is the result of hyperplasia [51]. Both pink peroxisome and red organic molecule processes show moderate diet-by-strain clustering.…”

“…High fat diet has been shown to alter brown adipose activity and blunt its positive effects on systemic metabolism [65,66]. Yet, as illustrated by numerous studies, dietary response is heavily dependent on genetic background [16,17,73–75,50,51,67–72]. Here we present the first study on the effects of genetic background and diet on brown adipose transcriptional networks associating with metabolic variation.…”

“…The LG/J and SM/J strains are frequently used in metabolic studies because they vary in their metabolic response to dietary fat [50,58,59,76,77]. We recently demonstrated that high fat-fed SM/J mice dramatically expand their interscapular brown adipose depots and that contemporary with this expansion, mice enter diabetic remission [51]. Understanding the genetic underpinnings of this phenomenon could open new avenues for understanding novel biology and highlight therapeutic targets for obesity-related metabolic dysfunction.…”

“…These strains both respond to a high fat diet with obesity, elevated fasting glucose, and impaired glucose tolerance at 20 weeks of age [50]. However, by 30 weeks, high fat-fed SM/J mice resolve their glycemic dysfunction [51]. This occurs concurrently with a dramatic expansion of their interscapular brown adipose depots, making SM/J mice a unique and intriguing model system in which to investigate brown adipose transcriptional networks, how they correlate with metabolic traits, and how they are affected by dietary environment.…”