Txnip, Tanycytes, and Torpor

Abstract

As biologists, we are brought up with the concept that mammals are homeothermic, so they tightly regulate body temperature through a complex balance between thermogenesis and heat conservation and dissipation mechanisms. One of the remarkable features of the natural world is that many mammals can also show torpor or hibernation. They can change the parameters of this homeostatic process, and either undergo daily (torpor) or extended periods (hibernation) when body temperature falls towards ambient environmental values. Homeostasis, therefore, becomes rheostasis (1), yet neural and peripheral tissues retain their functional integrity despite marked hypoxia and hypoglcemia. We do not understand fully how this profound change in physiology comes about, but in the current issue of Endocrinology, evidence is provided that up-regulation of thioredoxin-interacting protein (Txnip) in the ependymal cell layer of the hypothalamus is associated with this process (2). Previous studies have suggested that Txnip expressed in the mediobasal hypothalamus plays a role in nutrient sensing (3) and may specifically regulate leptin sensitivity in neuropeptide Y/agouti-related peptide neurons (4). Intriguingly, the current study indicates that enhanced expression is likely to be occurring within tanycyte cells (Figure 1). This is a very timely observation, because there is a growing interest in the role of these cells both in nutrient sensing (5) and as regulators of hypothalamic neurogenesis (6–8) and plasticity (9, 10) that may underlie long-term changes in appetite and energy expenditure. Torpor can occur for a number of reasons in small mammals. Commonly, it is an adaptation to survive winter in temperate or arctic environments, but it can also occur as a response to severely limited food supply or caloric restriction, or to acute cold exposure. Hand et al (2) initially found up-regulation of Txnip in a transgenic mouse lacking the G-protein coupled receptor (GPR50) orphan receptor, which readily enters torpor in response to mild fasting, perhaps reflecting a deficit in hypothalamic nutrient sensing (11). They then found that up-regulation of hypothalamic Txnip occurred in all the various natural types of torpor: seasonal torpor in the Siberian hamster, Phodopus sungorus, torpor in wild-type mice during prolonged fasting and cold exposure, and also in a pharmacological model where mice were treated with 2-deoxyglucose to inhibit glycolysis. Up-regulation of Txnip, therefore, appears to be a universal feature of torpor, although whether it is causal in generating the hypothermic state or is a downstream consequence of torpor has not yet been resolved. The authors note that transgenic mice lacking Txnip fail to enter torpor when fasted for 24 hours, supporting a causal role, and they suggest that its role is to reduce whole-body energy expenditure in order to sustain the hypothermic and hypometabolic state. This concept is supported by their observation that Txnip expression is also elevated in some peripheral tissues during torpor, in particular in brown adipose tissue. Most tellingly, the authors note previous studies showing that transgenic mice lacking Txnip die during a prolonged fast (12), implying that Txnip has a protective function during the extreme hypometabolic state experienced during torpor, which is critical for survival of periods of drastically reduced food availability. Perhaps the most interesting aspect of the current study is that it refocuses attention on tanycytes as a key anatomical substrate for the regulation of energy metabolism. The authors themselves are circumspect as to whether the Txnip gene expression in the ependymal cell layer as identified by in situ hybridization is actually in tanycyte cells.