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.
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...
Objectives: Life history theory, a branch of evolutionary theory, predicts the existence of trade-offs in energetic allocation between competing physiological functions. The core metabolic cost of self-maintenance, measured by resting metabolic rate (RMR), represents a large component of human daily energy expenditure.Despite strong selective pressures for energetic frugality and high observed interindividual variation in RMR, the link between RMR and energetic allocation to lifehistory traits remains understudied in humans.Materials: In a sample of 105 (m = 57, f = 48), we investigated the relationship between adult RMR and investment in growth quality, as measured by fluctuating asymmetry (FA).Results: Measurement of RMR and FA in university rowers revealed a significant positive correlation amongst males (n = 57, r = 0.344, p = 0.005, 1-tailed; standardized 95% CI, 0.090 to 0.598). Convincing evidence for a correlation among females was not found (n = 48, r = 0.142, p = 0.169, 1-tailed, standardized 95% CI, −0.152 to 0.435). Discussion:The data suggest that low-quality asymmetrical growth is associated with later-life metabolic inefficiencies in males. Energetic investment in processes (likely concerning the stress-response) unrelated to growth during childhood may thereby trade-off against adult metabolic efficiency. We suggest that the presence of a relationship between RMR and FA in males but not females may be explained by the additional metabolic strain associated with larger body size and increased male muscularity, which may amplify the inefficiencies arising from low-quality growth.
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