Glucocorticoid-Induced Obesity Develops Independently of UCP1

Luijten, Ineke; Brooks, K.N.; Boulet, Nathalie; Shabalina, Irina G.; Jaiprakash, Ankita; Carlsson, Bo; Fischer, Alexander W.; Cannon, Barbara; Nedergaard, Jan

doi:10.1016/j.celrep.2019.04.041

Cited by 55 publications

(74 citation statements)

References 45 publications

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“…One limitation of our study is that our mouse experiments were conducted at 22°C, which is below thermoneutrality for mice [34]. A recent investigation provides evidence that UCP1 protein levels are reduced 100fold by corticosterone treatment in mice housed 30°C but not at 22°C [35]. Thus, there may still be an effect of BAT-specific GR KO at thermoneutrality (30°C for mice), which we could not test in our study.…”

Section: Discussionmentioning

confidence: 84%

“…In this respect, our genetic loss-of-function study now addresses a key question in the field of BAT research and GR-dependent endocrine control of metabolism by demonstrating that in contrast to previous assumptions, the GR in BAT is largely dispensable for systemic energy homeostasis during both short and long-term metabolic adaptations. A recent investigation provides evidence that UCP1 protein levels are reduced 100fold by corticosterone treatment in mice housed 30°C but not at 22°C [35]. A recent investigation provides evidence that UCP1 protein levels are reduced 100fold by corticosterone treatment in mice housed 30°C but not at 22°C [35].…”

Section: Discussionmentioning

confidence: 99%

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The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis

et al. 2019

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Aberrant activity of the glucocorticoid (GC)/glucocorticoid receptor (GR) endocrine system has been linked to obesity-related metabolic dysfunction. Traditionally, the GC/GR axis has been believed to play a crucial role in adipose tissue formation and function in both, white (WAT) and brown adipose tissue (BAT). While recent studies have challenged this notion for WAT, the contribution of GC/GR signaling to BAT-dependent energy homeostasis remained unknown. Here, we have generated and characterized a BATspecific GR-knockout mouse (GR BATKO ), for the first time allowing to genetically interrogate the metabolic impact of BAT-GR. The HPA axis in GR BATKO mice was intact, as was the ability of mice to adapt to cold. BAT-GR was dispensable for the adaptation to fasting-feeding cycles and the development of diet-induced obesity. In obesity, glucose and lipid metabolism, insulin sensitivity, and food intake remained unchanged, aligning with the absence of changes in thermogenic gene expression. Together, we demonstrate that the GR in UCP1-positive BAT adipocytes plays a negligible role in systemic metabolism and BAT function, thereby opposing a longstanding paradigm in the field.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis

et al. 2019

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“…Mitochondria were isolated from brown adipose tissue as described (Fischer et al, 2017;Luijten et al, 2019;Shabalina et al, 2013). Briefly, iBAT and scBAT of 2 mice were pooled in ice-cold isolation buffer (0.25 M sucrose buffer, 5 mM Tris pH 7.4, 2 mM EGTA, 2 % BSA).…”

Section: Isolation Of Mitochondria From Brown Adipose Tissuementioning

confidence: 99%

Lipid Droplets in Brown Adipose Tissue Are Dispensable for Cold-Induced Thermogenesis

Chitraju

Fischer

Farese

et al. 2020

Preprint

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Brown adipocytes store metabolic energy as triglycerides (TG) in multilocular lipid droplets (LDs). Fatty acids released from brown adipocyte LDs by lipolysis are thought to activate and fuel UCP1-mediated thermogenesis. Here we test this hypothesis by preventing fatty acid storage in murine brown adipocytes through brown adipose tissue (BAT)-specific deletions of the TG synthesis enzymes, DGAT1 and DGAT2 (BA-DGAT KO). Despite the absence of LDs, BA-DGAT KO mice had functional BAT and maintained euthermia during acute or chronic cold exposure. As apparent adaptations to the lack of TG, brown adipocytes of BA-DGAT KO mice appear to utilize circulating glucose and fatty acids, as well as stored glycogen to fuel thermogenesis. Moreover, BA-DGAT KO mice were resistant to diet-induced glucose intolerance, likely due to increased glucose disposal by BAT. Thus, surprisingly, TGs in BAT are dispensable for its function, in part through adaptations to utilize other fuel sources.

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“…To further highlight the interaction of sex, 172 temperature, and diet in short-term weight gain and type of weight gained, Figure 2C displays 173 the one week change in body weight as the components of FM and FFM gained. The metabolic 174 efficiency was calculated as the sum of the stored energy from change in FM and lean mass 175 divided by EI ( Figure 2D) [26]. Calculated percent metabolic efficiency shows a similar pattern to the FM data ( Figure 2A).…”

Section: Changes In Body Composition 161mentioning

confidence: 64%

“…FI, EI, and EB data during HFHS feeding from two 20⁰C female mice was not 87 included in data analysis due to excessive food spillage. Percent metabolic efficiency was 88 calculated as: (change in fat mass (kcal) + change in lean mass (kcal)/EI, where the energy 89 content for fat and lean mass was 9.32 kcal/g & 1.19 kcal/g, respectively [26]. Thermic effect of 90 food (TEF) was determined from the consensus thermic effect of food for fat (2.5%), 91 carbohydrate (7.5%), and protein (25%), and the manufacturer provided diet information for 92 each diet [27,28].…”

Section: Indirect Calorimetry Energy Metabolism and Behavior Analysis 69mentioning

confidence: 99%

Divergent Energy Expenditure Impacts Mouse Metabolic Adaptation to Acute High-Fat/High-Sucrose Diet Producing Sexually Dimorphic Weight Gain Patterns

Morris

Noland

Allen

et al. 2019

Preprint

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Highlights Utilized ambient temperature differences as an experimental tool to study the impact of divergent baseline energy expenditure on metabolic adaptation to high-fat, high-sucrose diet. Baseline energy expenditure and sex interact to impact diet-induced changes in body composition and weight gain. The energy expenditure and sex interaction is a result of an inverse relationship between fat mass gain and weight-adjusted total energy expenditure, as well as, diet-induced non-shivering thermogenesis. These data support that the hypothesis that higher energy expenditure amplifies the coupling of energy intake to energy expenditure during energy dense feeding, resulting in reduced positive energy balance and reduced gains in weight and adiposity. First evidence that energy expenditure level plays a role in the composition of weight gained by female mice during acute HFHS feeding. This study further highlights issues with obesity/energy metabolism research performed in mice at sub-thermoneutral housing temperatures, particularly with sex comparisons. GRAPHIC ABSTRACTLegend: Male and female mice housed at 30⁰C had lower energy expenditure (EE) & energy intake (EI), while having greater energy balance (EB), during 7-day high-fat/high-sucrose (HFHS) feeding compared to male and female mice, respectively, housed at 20⁰C. However, female mice had lower EB compared to males at both housing temperature. Female mice housed at 30⁰C gained less weight than 30⁰C males but gained the same relative amount of fat mass during acute HFHS feeding. Interestingly, 20⁰C females gained the same amount of weight as 20⁰C males but gained primarily fat-free mass, while the males gained the same proportion of fat as 30⁰C males and females. ABSTRACT 1Objective: Long-term weight gain can result from cumulative small weight increases due to 2 short-term excess caloric intake during weekends and holidays. Increased physical activity may 3 mediate weight gain through increases in energy expenditure (EE) and reductions in energy 4 balance. Current methods for modulating mouse EE (e.g. -exercise, chemical uncouplers, etc.) 5 have confounding effects. However, it is known that mouse EE linearly increases as housing 6 temperature decreases below the thermoneutral zone. Methods: To determine how robust 7 differences in baseline EE impact 7-day changes in weight and body composition on low-fat and 8 high-fat, high-sucrose (HFHS) diets, we performed indirect calorimetry measurements in male 9 and female mice housed at divergent temperatures (20⁰C vs. 30⁰C). Results: As expected, 10 mice housed at 30⁰C have ~40% lower total EE and energy intake compared to 20⁰C mice 11 regardless of diet or sex. Energy balance was increased with HFHS in all groups, with ~30% 12 greater increases observed in 30⁰C versus 20⁰C mice. HFHS increased weight gain regardless 13 of temperature or sex. Interestingly, no HFHS-induced weight gain differences were observed 14 between females at different temperatures. In contrast, 30⁰C male mice on HFHS gained ~50% 15 more...

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Glucocorticoid-Induced Obesity Develops Independently of UCP1

Cited by 55 publications

References 45 publications

The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis

The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis

Lipid Droplets in Brown Adipose Tissue Are Dispensable for Cold-Induced Thermogenesis

Divergent Energy Expenditure Impacts Mouse Metabolic Adaptation to Acute High-Fat/High-Sucrose Diet Producing Sexually Dimorphic Weight Gain Patterns

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