FP34-3 Thyroid hormone signalling is associated with resistance to diet-induced obesity and metabolic plasticity in WSB/EiJ mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP34-Molecular Mechanisms in Thyroid Hormone Action & Cancer
Basic/Translational
Monday, June 17, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 10:55 AM
Room 103 (Moscone Center)

Poster Board MON-416
James Bowers*1, Jérémy Terrien1, Isabelle Seugnet1, Raphaël Denis2, Serge Luquet2, Marie-Stéphanie Clerget-Froidevaux1 and Barbara Demeneix1
1MNHN / CNRS UMR7221, Paris, France, 2Université Paris Diderot-Paris 7, Paris, France
The wild-type derived strain of laboratory mice, WSB/EiJ, is resistant to diet-induced obesity (DIO) (1). Although euthyroid, it has lower than average serum total T4 (2). Given the role of thyroid hormones (TH) in metabolic control, we tested the hypothesis that these phenotypic characteristics are inter-dependent. Endocrine and metabolic responses were measured in 3-month old male C57BL/6J and WSB/EiJ mice on different diets: control (10% Kcal from fat), short-term or long-term high fat diet (HFD) (3 day or 8 week 45% Kcal from fat, respectively).

Both body weight and hormonal profiling during the 8-week diet treatment confirmed the reported resistance to DIO and low T4 in WSB/EiJ compared to C57BL/6J mice. In particular, T3:T4 ratios were stable in C57BL/6J mice on all diets whereas they increased in HFD fed WSB/EiJ, reflecting adaptability of the hypothalamo-pituitary-thyroid axis (HPT) in WSB/EiJ mice. Control of TH availability is being characterised by deiodinase activity assays in different tissues.

Indirect calorimetry showed that HFD-treated WSB/EiJ mice remain resistant to DIO, despite moving less and eating more. In addition, control fed WSB/EiJ mice displayed a strong circadian substrate-switching capacity that was dampened, but maintained, under HFD. Remarkably, WSB/EiJ mice switched from strict lipid usage at ZT8, to high carbohydrate oxidation during the feeding period, even achieving de novo lipogenesis. This shift in substrate usage was confirmed by greater glucose tolerance of WSB/EiJ than C57BL/6J at ZT1, an effect that was inverted at ZT8.

To investigate mitochondrial roles in the differential metabolic responses, we used mitochondrial respiration analyses (Seahorse Bioscience) and transmission electron microscopy (TEM). Transcriptomic analysis (RNAseq) on RNA from laser capture microdissected hypothalamic paraventricular nucleus (PVN) is being exploited to compare gene networks involved in central regulation of metabolism in the two strains.

The whole-body characterisation and large-scale transcriptomic analyses in our study will provide a better understanding of the mechanisms underlying the links between TH set-points and central control of metabolism. We propose that the reported extreme longevity of WSB/EiJ mice (2) could be linked to the TH-associated metabolic plasticity of this strain.

(1) Lee, K.T.Y., Karunakaran, S., Ho, M.M., Clee, S.M., 2011. PWD/PhJ and WSB/EiJ mice are resistant to diet-induced obesity but have abnormal insulin secretion. Endocrinology 152, 3005-3017. (2) Yuan, R., Tsaih, S.W., Petkova, S.B., Marin de Evsikova, C., Xing, S., Marion, M.A., Bogue, M.A., Mills, K.D., Peters, L.L., Bult, C.J., Rosen, C.J., Sundberg, J.P., Harrison, D.E., Churchill, G.A., Paigen, B., 2009. Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 8, 277-287.

Nothing to Disclose: JB, JT, IS, RD, SL, MSC, BD

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

Sources of Research Support: Supported by EU FP7/2007-2013 grants: SWITCHBOX Collaborative Project and NINA International Training Network.