http://informahealthcare.com/erc ISSN: 0743-5800 (print), 1532-4206 (electronic) Endocr Res, Early Online: 1–6 ! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/07435800.2013.833216 ORIGINAL ARTICLE They live in the land down under: thyroid function and basal metabolic rate in the Blind Mole Rat, Spalax Aaron Avivi 1 , Eviatar Nevo 1 , Keren Cohen 2,3 , Nick Sotnichenko 4 , Aleck Hercbergs 5 , Mark Band 6 , Paul J. Davis 7,8 , Martin Ellis 2 , and Osnat Ashur-Fabian 2,3 1 Institute of Evolution, University of Haifa, Haifa, Israel, 2 Translational Hemato-Oncology, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel, 3 The Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel, 4 Veterinary Services, Research Authority, University of Haifa, Haifa, Israel, 5 Radiation Oncology, Cleveland Clinic, Cleveland, Ohio, USA, 6 The W.M. Keck Center for Comparative and Functional Genomics, Illinois University, Urbana, IL, USA, 7 Albany Medical College, Albany, New York USA, and 8 Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York Abstract The Israeli blind subterranean mole rat (Spalax ehrenbergi superspecies) lives in sealed underground burrows under extreme, hypoxic conditions. The four Israeli Spalax allospecies have adapted to different climates, the cool–humid (Spalax galili,2 n ¼ 52 chromosomes), semihumid (S. golani,2 n ¼ 54) north regions, warm–humid (S. carmeli,2 n ¼ 58) central region and the warm–dry S. judaei,2 n ¼ 60) southern regions. A dramatic interspecies decline in basal metabolic rate (BMR) from north to south, even after years of captivity, indicates a genetic basis for this BMR trait. We examined the possibility that the genetically-conditioned interspecies BMR difference was expressed via circulating thyroid hormone. An unexpected north to south increase in serum free thyroxine (FT4) and total 3, 5, 3 0 -triiodo-L-thyronine (T3) (p50.02) correlated negatively with previously published BMR measurements. The increases in serum FT4 and T3 were symmetrical, so that the T3:FT4 ratio – interpretable as an index of conversion of T4 to T3 in nonthyroidal tissues – did not support relative decrease in production of T3 as a contributor to BMR. Increased north-to-south serum FT4 and T3 levels also correlated negatively with hemoglobin/hematocrit. North-to-south adaptations in spalacids include decreased BMR and hematocrit/hemoglobin in the face of increasing thyroid hormone levels, arguing for independent control of hormone secretion and BMR/hematocrit/hemoglobin. But the significant inverse relationship between thyroid hormone levels and BMR/hematocrit/ hemoglobin is also consistent with a degree of cellular resistance to thyroid hormone action that protects against hormone-induced increase in oxygen consumption in a hostile, hypoxic environment. Keywords BMR, free T4, hematocrit, Spalax, total T3 History Received 24 April 2013 Revised 3 August 2013 Accepted 5 August 2013 Published online 23 September 2013 Introduction The Israeli blind subterranean mole rats (Figure 1A) are wild territorial and solitary mammals which belong to the super- species Spalax ehrenbergi and spend their life solely in sealed underground burrows (1). The Spalax superspecies consists of at least 12 allospecies in the Near East, from which four reside in Israel (1,2) (Figure 1B). In the north, Spalax galili (2 n ¼ 52 chromosomes) inhabits the cool–humid Upper Galilee Mountains and Spalax golani (2 n ¼ 54), in the cool, semihumid Golan Heights; Spalax carmeli (2 n ¼ 58), in the warm–humid central Israel; and the southernmost species Spalax judaei (2 n ¼ 60), in the warm–dry desert regions, at which reside two populations, Anza and Lahav. Over the past 40 million years, Spalax has evolved complex physiological and genetic strategies to cope with hypoxia more efficiently than any other mammalian species (3–10). Spalax has a low basal metabolic rate (BMR) and its resting heart rate and cardiac output are lower than the values predicted from its body mass (11). The thyroid gland is structurally and functionally con- served in vertebrates (12) and plays important roles in the regulation of thermogenesis, body temperature and cellular metabolism via the production of L- thyroxine (T4) that is converted by deiodination in tissues to metabolically active 3, 5, 3 0 -triiodo-L-thyronine (T3). In the current studies, we measured circulating thyroid hormone levels in Spalax to determine if a decrease in thyroid function (hypothyrodism) contributed to the north-to-south decrease in interspecies BMR or in oxygen-carrying capacity (hematocrit/hemoglo- bin). We examined plasma osmolality in the animals, seeking a specific tissue (kidney) index of the possibility that hypothyroidism was present in the animals living in the south. Free water clearance impairment with hypo-osmolality Correspondence: Osnat Ashur-Fabian, The Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Tel: +972-9-7472178. Fax: +972- 97471971. E-mail: osnataf@gmail.com Endocr Res Downloaded from informahealthcare.com by 194.114.146.227 on 09/28/13 For personal use only.