Long-Term Cold Adaptation Does Not Require FGF21 or UCP1

Keipert, Susanne; Kutschke, Maria; Ost, Mario; Schwarzmayr, Thomas; Schothorst, Evert M. van; Lamp, Daniel; Brachthäuser, Laura; Hamp, Isabel; Mazibuko, Sithandiwe E.; Hartwig, Sonja; Lehr, Stefan; Graf, Elisabeth; Plettenburg, Oliver; Neff, Frauke; Tschöp, Matthias H.; Jastroch, Martin

doi:10.1016/j.cmet.2017.07.016

Cited by 108 publications

(101 citation statements)

References 45 publications

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“…The disconnect between thermogenic genes and cold tolerance in the current study supports other work showing that browning is not necessary for thermoregulation or the regulation of whole‐body glucose and lipid metabolism (1, 28, 40–44). For example, large increases in iWAT Ucp1 expression following chronic treatment with CL316,243 are not associated with increased glucose or fatty acid uptake by this tissue (29).…”

Section: Discussionsupporting

confidence: 90%

Loss of glucagon signaling alters white adipose tissue browning

et al. 2019

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Various endocrine factors contribute to cold‐induced white adipose tissue (WAT) browning, but glucagon has largely been ignored. The purpose of the current investigation was to determine if glucagon was required for the effects of cold on WAT browning. Utilizing whole‐body glucagon receptor knockout (Gcgr−/−) mice and their wild‐type (WT) littermate controls, we examined the response of inguinal WAT (iWAT) and interscapular brown adipose tissue (BAT) to an acute (48 h) cold stress or challenge with the β3‐adrenergic agonist CL316,243. The effects of glucagon alone on the induction of thermogenic genes in adipose tissue from C57BL6/J mice were also examined. Gcgr−/− mice displayed modest increases in indices of browning at room temperature while displaying a blunted induction of Ucp1, Cidea, and Ffg21 mRNA expression in iWAT following cold exposure. Similarly, cold induced increases in mitochondrial DNA copy number, and the protein content of mitochondrial respiratory chain complexes, UCP1, and PGC1α were attenuated in iWAT from Gcgr−/− mice. In BAT, the induction of thermogenic markers following cold exposure was reduced, but the effect was less pronounced than in iWAT. Glucagon treatment increased the expression of thermogenic genes in both iWAT and BAT of C57BL6/J mice. In response to CL316,243, circulating fatty acids, glycerol, and the phosphorylation of hormone‐sensitive lipase were attenuated in iWAT of Gcgr−/− mice. We provide evidence that glucagon is sufficient for the induction of thermogenic genes in iWAT, and the absence of intact glucagon signaling blunts the cold‐induced browning of WAT, possibly due, in part, to impaired adrenergic signaling.—Townsend, L. K., Medak, K. D., Knuth, C. M., Peppier, W. T., Charron, M. J., Wright, D. C. Loss of glucagon signaling alters white adipose tissue browning. FASEB J. 33, 4824–4835 (2019). http://www.f asebj.org

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Section: Discussionsupporting

confidence: 90%

Loss of glucagon signaling alters white adipose tissue browning

et al. 2019

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“…6, our results suggest that the Fgf21‐Ucp1 axis is engaged by MD only in male mice, and may be dispensable for the metabolic benefits of MD in females as female mice derive these benefits despite unchanged plasma Fgf21 levels and Ucp1 gene expression. Alternatively, MD may promote metabolic health in both sexes through Fgf21‐Ucp1–independent mechanisms, as was recently found to be true in the case of cold‐induced thermogenesis (48, 49). Our results have also revealed sexually dimorphic effects of MD on hepatic gene expression, particularly with respect to the regulation of lipid metabolism.…”

Section: Discussionmentioning

confidence: 79%

“…This observation suggests that although mice of both sexes fed MD diets have increased energy expenditure, the mechanism linking MR to increased energy expenditure may be independent of Fgf21 and Ucp1 , at least in females. Recent work has demonstrated that cold‐induced thermogenesis is also mediated by a Fgf21‐Ucp1 independent mechanism (48, 49). Further research is needed to specifically identify the biologic basis for the increased energy expenditure induced by MD in both males and females.…”

Section: Discussionmentioning

confidence: 99%

Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

Yang

Miller

et al. 2018

FASEB j.

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Obesity and diabetes are major challenges to global health, and there is an urgent need for interventions that promote weight loss. Dietary restriction of methionine promotes leanness and improves metabolic health in mice and humans. However, poor long-term adherence to this diet limits its translational potential. In this study, we develop a short-term methionine deprivation (MD) regimen that preferentially reduces fat mass, restoring normal body weight and glycemic control to diet-induced obese mice of both sexes. The benefits of MD do not accrue from calorie restriction, but instead result from increased energy expenditure. MD promotes increased energy expenditure in a sex-specific manner, inducing the fibroblast growth factor (Fgf)-21-uncoupling protein (Ucp)-1 axis only in males. Methionine is an agonist of the protein kinase mechanistic target of rapamycin complex (mTORC)-1, which has been proposed to play a key role in the metabolic response to amino acid-restricted diets. In our study, we used a mouse model of constitutive hepatic mTORC1 activity and demonstrate that suppression of hepatic mTORC1 signaling is not required for the metabolic effects of MD. Our study sheds new light on the mechanisms by which dietary methionine regulates metabolic health and demonstrates the translational potential of MD for the treatment of obesity and type 2 diabetes.-Yu, D., Yang, S. E., Miller, B. R., Wisinski, J. A., Sherman, D. S., Brinkman, J. A., Tomasiewicz, J. L., Cummings, N. E., Kimple, M. E., Cryns, V. L., Lamming, D. W. Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms.

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“…The Seahorse Extracellular Flux Analyzer is a prevalent approach to measuring the oxygen consumption rate (OCR) of isolated adipocytes [11,12], and it has been reported that the OCR of brown adipocytes increases after the activation of thermogenesis by norepinephrine (NE) treatment [13]. Other measurements such as blood flow, food intake and locomotor activity [19][20][21] are all short of specificity and are incapable of distinguishing the metabolism of brown and beige fat from that of the entire organism. Thermal imaging allows noninvasive measurement of the temperature change in BAT during thermogenesis.…”

Section: Introductionmentioning

confidence: 99%

In vivo study of metabolic dynamics and heterogeneity in brown and beige fat by label‐free multiphoton redox and fluorescence lifetime microscopy

Wei

Qin

et al. 2019

Journal of Biophotonics

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In this work, the metabolic characteristics of adipose tissues in live mouse model were investigated using a multiphoton redox ratio and fluorescence lifetime imaging technology. By analyzing the intrinsic fluorescence of metabolic coenzymes, we measured the optical redox ratios of adipocytes in vivo and studied their responses to thermogenesis. The fluorescence lifetime imaging further revealed changes in protein bindings of metabolic coenzymes in the adipocytes during thermogenesis. Our study uncovered significant heterogeneity in the cellular structures and metabolic characteristics of thermogenic adipocytes in brown and beige fat. Subgroups of brown and beige adipocytes were identified based on the distinct lipid size distributions, redox ratios, fluorescence lifetimes and thermogenic capacities. The results of our study show that this label-free imaging technique can shed new light on in vivo study of metabolic dynamics and heterogeneity of adipose tissues in live organisms. K E Y W O R D Sbeige fat, fluorescence lifetime, optical redox ratio, thermogenesis

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Long-Term Cold Adaptation Does Not Require FGF21 or UCP1

Cited by 108 publications

References 45 publications

Loss of glucagon signaling alters white adipose tissue browning

Loss of glucagon signaling alters white adipose tissue browning

Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

In vivo study of metabolic dynamics and heterogeneity in brown and beige fat by label‐free multiphoton redox and fluorescence lifetime microscopy

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