The contribution of thyroidal status in insulin signaling and glucose homeostasis has been implicated as a potential pathophysiological factor in humans, but the specific mechanisms remain largely elusive. Fasting induces changes in both thyroid hormone secretion and insulin signaling. Here, we explore how mammals that undergo natural, prolonged bouts of fasting provide unique insight into evolved physiological adaptations that allow them to tolerate such conditions despite intermittent states of reversible insulin resistance. Such insights from nature may provide clues to better understand the basis of thyroidal involvement in insulin dysregulation in humans.

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SUMMARYFood deprivation in mammals is typically associated with reduced thyroid hormone (TH) concentrations and deiodinase content and activity to suppress metabolism. However, in prolonged-fasted, metabolically active elephant seal pups, TH levels are maintained, if not elevated. The functional relevance of this apparent paradox is unknown and demonstrates variability in the regulation of TH levels, metabolism and function in food-deprived mammals. To address our hypothesis that cellular TH-mediated activity is upregulated with fasting duration, we quantified the mRNA expression and protein content of adipose and muscle deiodinase type I (DI1) and type II (DI2), and TH receptor beta-1 (THrβ-1) after 1, 3 and 7 weeks of fasting in northern elephant seal pups (N=5-7 per week). Fasting did not decrease the concentrations of plasma thyroid stimulating hormone, total triiodothyronine (tT 3 ), free T 3 , total thyroxine (tT 4 ) or free T 4 , suggesting that the hypothalamic-pituitary-thyroid axis is not suppressed, but rather maintained during fasting. Mean mRNA expression of adipose DI1 and DI2 increased threefold and fourfold, respectively, and 20-and 30-fold, respectively, in muscle. With the exception of adipose DI1, protein expression of adipose DI2 and muscle DI1 and DI2 increased twofold to fourfold. Fasting also increased adipose (fivefold) and muscle (fourfold) THrβ-1 mRNA expression, suggesting that the mechanisms mediating cellular TH activity are upregulated with prolonged fasting. The data demonstrate a unique, atypical mechanism of TH activity and regulation in mammals adapted to prolonged food deprivation in which the potential responsiveness of peripheral tissues and cellular TH activity are increased, which may contribute to their lipid-based metabolism.Key words: lipid metabolism, reverse T3, seal, thyroxine, triiodothyronine. THE JOURNAL OF EXPERIMENTAL BIOLOGY 4648 concentration in hibernating ground squirrels results from reduced TH metabolism, accompanied by a reduction in nuclear receptors, suggesting that TH function is suppressed despite the increase in circulating levels (i.e. cryptically hyperthyroid) (Magnus and Henderson, 1988a;Magnus and Henderson, 1988b). Such variability in the regulation of TH levels and function in food-deprived mammals demonstrates the diversity of TH physiology during periods of acute or chronic food deprivation, and highlights the necessity to perform more comprehensive studies into the functional relevance of these differences.Northern elephant seals, Mirounga angustirostris (Gill 1866), naturally fast from food and water for up to 3 months while on land (Ortiz et al., 1978; Crocker et al., 1998;Le Boeuf and Laws, 1994), and during the post-weaning fast, oxidation of non-esterified fatty acids (NEFAs) accounts for approximately 95% of the pup's metabolic rate (Ortiz et al., 1978;Viscarra et al., 2012). The fasting metabolism of seals is primarily dependent on lipid oxidation (Crocker et al., 1998;Pramfalk et al., 2011; Crocker et al., 2012a; Crocker et al., 2012...

Hyperglycemia increases the risk of oxidant overproduction in the heart through activation of a multitude of pathways. Oxidation of mitochondrial enzymes may impair their function resulting in accumulation of intermediates and reverse electron transfer, contributing to mitochondrial dysfunction. Furthermore, the renin-angiotensin system (RAS) becomes inappropriately activated during metabolic syndrome, increasing oxidant production. To combat excess oxidant production, the transcription factor, nuclear factor erythriod-2- related factor 2 (Nrf2), induces expression of many antioxidant genes. We hypothesized that angiotensin II receptor type 1 (AT1) blockade improves mitochondrial function in response to an acute glucose load via upregulation of Nrf2. To address this hypothesis, an oral glucose challenge was performed in three groups prior to dissection (n = 5–8 animals/group/time point) of adult male rats: 1) Long Evans Tokushima Otsuka (LETO; lean strain-control), 2) insulin resistant, obese Otsuka Long Evans Tokushima Fatty (OLETF), and 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 6 weeks). Hearts were collected at T0, T60, and T120 minutes post-glucose infusion. ARB increased Nrf2 binding 32% compared to OLETF at T60. Total superoxide dismutase (SOD) and catalase (CAT) activities were increased 45% and 66% respectively in ARB treated animals compared to OLETF. Mitochondrial enzyme activities of aconitase, complex I, and complex II increased by 135%, 33% and 66%, respectively in ARB compared to OLETF. These data demonstrate the protective effects of AT1 blockade on mitochondrial function during the manifestation of insulin resistance suggesting that the inappropriate activation of AT1 during insulin resistance may impair Nrf2 translocation and subsequent antioxidant activities and mitochondrial function.

EA, used alone or in combination with other therapies, such as Chinese herbs or diet-exercise interventions, has the potential to be an effective treatment for insulin resistance. Additional controlled clinical studies of acupuncture are needed in subjects with diabetes mellitus, ischaemic heart disease, muscle atrophy, and fatty liver disease.