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Homeostasis, the dominant explanatory framework for physiological regulation, has undergone significant revision in recent years, with contemporary models differing significantly from the original formulation. Allostasis, an alternative view of physiological regulation, goes beyond its homeostatic roots, offering novel insights relevant to our understanding and treatment of several chronic health conditions. Despite growing enthusiasm for allostasis, the concept remains diffuse, due in part to ambiguity as to how the term is understood and used, impeding meaningful translational and clinical research on allostasis. Here, we provide a more focused understanding of homeostasis and allostasis by explaining how both play a role in physiological regulation, and a critical analysis of regulation suggests how homeostasis and allostasis can be distinguished. Rather than focusing on changes in the value of a regulated variable (e.g., body temperature, body adiposity, or reward), research investigating the activity and relationship among the multiple regulatory loops that influence the value of these regulated variables may be the key to distinguishing homeostasis and allostasis. The mechanisms underlying physiological regulation and dysregulation are likely to have important implications for health and disease.

This tribute to Bart Hoebel briefly reviews the following topics. Metabolic processes are intimately intertwined with food intake as well as drug taking. Changes in any of these processes can be adequately adjusted to the environment to preclude major perturbations in homeostatically-regulated systems, but only if the environment is predictable. Learning plays a critical role in adapting these processes to specific situations. The regulatory context plays a critical role in how metabolism and food intake interact., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Curt Richter introduced behavioral control into the concept of homeostasis, thereby opening entire fields of research. The prevailing dogma, and the techniques he used, conspired to lead Richter and others to interpret regulation in strict negative feedback terms. Although this point of view continues to be embraced by many contemporary biologists, we believe that prevailing sentiment favors a broader view in which organisms integrate anticipatory pre-emptive control over regulated variables whenever possible.

Contrary to dogma, much physiological regulation utilizes learning from past experience to make responses that preemptively and effectively neutralize anticipated regulatory challenges. Understanding physiological regulation therefore requires expanding explanatory models beyond homeostasis and allostasis to emphasize the prominence of conditioning. [ABSTRACT FROM AUTHOR]

Initial administration of ≥60% nitrous oxide (N 2 O) to rats promotes hypothermia primarily by increasing whole-body heat loss. We hypothesized that the drug promotes heat loss via the tail and might initially inhibit thermogenesis via brown adipose tissue (BAT), major organs of thermoregulation in rodents. Following repeated administrations, N 2 O inhalation evokes hyperthermia underlain by increased whole-body heat production. We hypothesized that elevated BAT thermogenesis plays a role in this thermoregulatory sign reversal. Using dual probe telemetric temperature implants and infrared (IR) thermography, we assessed the effects of nine repeated 60% N 2 O administrations compared to control (con) administrations on core temperature, BAT temperature, lumbar back temperature and tail temperature. Telemetric core temperature, telemetric BAT temperature, and IR BAT temperature were reduced significantly during initial 60% N 2 O inhalation (p≤0.001 compared to con). IR thermography revealed that acute N 2 O administration unexpectedly reduced tail temperature (p=0.0001) and also inhibited IR lumbar temperature (p<0.0001). In the 9th session, N 2 O inhalation significantly increased telemetric core temperature (p=0.007) indicative of a hyperthermic sign reversal, yet compared to control administrations, telemetric BAT temperature (p=0.86), IR BAT temperature (p=0.85) and tail temperature (p=0.47) did not differ significantly. Thus, an initial administration of 60% N 2 O at 21 °C may promote hypothermia via reduced BAT thermogenesis accompanied by tail vasoconstriction as a compensatory mechanism to limit body heat loss. Following repeated N 2 O administrations rats exhibit a hyperthermic core temperature but a normalized BAT temperature, suggesting induction of a hyperthermia-promoting thermogenic adaptation of unknown origin. [ABSTRACT FROM AUTHOR]

Abstract: Direct animal calorimetry, the gold standard method for quantifying animal heat production (HP), has been largely supplanted by respirometric indirect calorimetry owing to the relative ease and ready commercial availability of the latter technique. Direct calorimetry, however, can accurately quantify HP and thus metabolic rate (MR) in both metabolically normal and abnormal states, whereas respirometric indirect calorimetry relies on important assumptions that apparently have never been tested in animals with genetic or pharmacologically-induced alterations that dysregulate metabolic fuel partitioning and storage so as to promote obesity and/or diabetes. Contemporary obesity and diabetes research relies heavily on metabolically abnormal animals. Recent data implicating individual and group variation in the gut microbiome in obesity and diabetes raise important questions about transforming aerobic gas exchange into HP because 99% of gut bacteria are anaerobic and they outnumber eukaryotic cells in the body by ∼10-fold. Recent credible work in non-standard laboratory animals documents substantial errors in respirometry-based estimates of HP. Accordingly, it seems obvious that new research employing simultaneous direct and indirect calorimetry (total calorimetry) will be essential to validate respirometric MR phenotyping in existing and future pharmacological and genetic models of obesity and diabetes. We also detail the use of total calorimetry with simultaneous core temperature assessment as a model for studying homeostatic control in a variety of experimental situations, including acute and chronic drug administration. Finally, we offer some tips on performing direct calorimetry, both singly and in combination with indirect calorimetry and core temperature assessment. [Copyright &y& Elsevier]

Abstract: Changes in typical whole-animal dependent variables following drug administration represent an integral of the drug''s pharmacological effect, the individual''s autonomic and behavioral responses to the resulting disturbance, and many other influences. An archetypical example is core temperature (T c ), long used for quantifying initial drug sensitivity and tolerance acquisition over repeated drug administrations. Our previous work suggested that rats differing in initial sensitivity to nitrous oxide (N2O)-induced hypothermia would exhibit different patterns of tolerance development across N2O administrations. Specifically, we hypothesized that rats with an initially insensitive phenotype would subsequently develop regulatory overcompensation that would mediate an allostatic hyperthermic state, whereas rats with an initially sensitive phenotype would subsequently compensate to a homeostatic normothermic state. To preclude confounding due to handling and invasive procedures, a valid test of this prediction required non-invasive thermal measurements via implanted telemetric temperature sensors, combined direct and indirect calorimetry, and automated drug delivery to enable repeatable steady-state dosing. We screened 237 adult rats for initial sensitivity to 70% N2O-induced hypothermia. Thirty highly sensitive rats that exhibited marked hypothermia when screened and 30 highly insensitive rats that initially exhibited minimal hypothermia were randomized to three groups (n=10 each/group) that received: (1) twelve 90-min exposures to 70% N2O using a classical conditioning procedure, (2) twelve 90-min exposures to 70% N2O using a random control procedure for conditioning, or (3) a no-drug control group that received custom-made air. Metabolic heat production (via indirect calorimetry), body heat loss (via direct calorimetry) and T c (via telemetry) were simultaneously quantified during N2O and control gas administrations. Initially insensitive rats rapidly acquired (3rd administration) a significant allostatic hyperthermic phenotype during N2O administration whereas initially sensitive rats exhibited classical tolerance (normothermia) during N2O inhalation in the 4th and 5th sessions. However, the sensitive rats subsequently acquired the hyperthermic phenotype and became indistinguishable from initially insensitive rats during the 11th and 12th N2O administrations. The major mechanism for hyperthermia was a brisk increase in metabolic heat production. However, we obtained no evidence for classical conditioning of thermal responses. We conclude that the degree of initial sensitivity to N2O-induced hypothermia predicts the temporal pattern of thermal adaptation over repeated N2O administrations, but that initially insensitive and sensitive animals eventually converge to similar (and substantial) magnitudes of within-administration hyperthermia mediated by hyper-compensatory heat production. [Copyright &y& Elsevier]