OR45-1 Adrenocorticotrophin Hormone (ACTH) Rapidly Stimulates Brown Adipose Tissue Activity and Browning of White Adipose Tissue in Mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR45-HPA Axis
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:15 AM
Room 135 (Moscone Center)
Johanna C van den Beukel*1, Aldo Grefhorst1, Carmelo Quarta2, Jacobie Steenbergen1, Marc Lombes3, Patric JD Delhanty1, Roberta Mazza2, Uberto Pagotto2, Aart Jan van der Lely1 and Axel PN Themmen1
1Erasmus MC, Rotterdam, Netherlands, 2University of Bologna, Bologna, Italy, 3Fac de Medicine Paris-SUD, Le Kremlin-Bicetre, France
In mammals, white adipose tissue (WAT) stores energy as triglycerides, whereas brown adipose tissue (BAT) can generate heat by fatty acid oxidation, mediated by uncoupling protein 1 (UCP1). BAT activation and/or acquisition of BAT characteristics of WAT (i.e. browning) are suggested to combat obesity in human; however, therapeutic ways to activate BAT remain to be discovered. Cold exposure is commonly used to activate BAT in animal models, but is also accompanied with increased hypothalamus-pituitary-adrenal (HPA) axis activity. We hypothesized that HPA-axis hormones contribute to BAT activation and browning of WAT.

We investigated the role of ACTH and glucocorticoids on BAT and WAT in 4 models: cold-exposed mice; mouse brown adipocyte T37i cells; primary cultured murine BAT and inguinal WAT cells; and 18F-deoxyglucose (18F-FDG) positron emission tomography (PET) scans of ACTH-injected mice. In the cold-exposed mice we measured plasma ACTH and 24h fecal corticosterone levels and analyzed interscapular BAT and inguinal WAT. To study a direct effect of the HPA-hormones on BAT and WAT, we treated adipocytes with ACTH and dexamethasone. To test the direct effects of ACTH in vivo, we performed micro 18F-FDG-PET-scans.

Twenty-four hours of cold exposure resulted in: a 3.1-fold increase in Ucp1 mRNA expression in BAT (p=0.002); a 4-fold decrease in BAT lipid content (p=0.001); and increased intensity of UCP1 immunostaining.  Browning of inguinal WAT was confirmed by a 20-fold increase in Ucp1 mRNA expression (p=0.002), and increased UCP1 immunostaining. Cold exposure also enhanced the HPA-axis as serum ACTH (597 ± 112.8 vs 1203.7 ± 158.4 pg/mL, p= 0.03) and fecal corticosterone (117.7± 5.9  vs 219.9 ±16.7 ng/24h,  p=0.008) excretion doubled. In T37i cells, the glucocorticoid receptor agonist dexamethasone slightly suppressed Ucp1, whereas ACTH dose dependently induced Ucp1 expression and markedly increased glycerol release (p=0.03), indicative for enhanced lipolysis. In addition, ACTH elevated Ucp1 expression in cultured BAT (3-fold, p= 0.03) and inguinal WAT (3.7-fold, p=0.01) primary cells. Finally, a single ACTH bolus doubled 18F-FDG uptake by interscapular BAT of mice (p=0.02).

In conclusion, our results suggest that ACTH can directly activate brown adipocytes and promote browning of inguinal WAT in mice. Stimulation of the HPA axis upon cold exposure may therefore play an important role in the induction of BAT activity and browning of WAT.

Nothing to Disclose: JCV, AG, CQ, JS, ML, PJD, RM, UP, AJV, APT

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

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