Physiology and relevance of human adaptive thermogenesis response Francesco S. Celi, Trang N. Le, and Bin Ni Division of Endocrinology and Metabolism, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA In homoeothermic organisms, the preservation of core temperature represents a primal function, and its costs in terms of energy expenditure can be considerable. In modern humans, the endogenous thermoregulation mechanisms have been replaced by clothing and envi- ronmental control, and the maintenance of thermoneu- trality has been successfully achieved by manipulation of the micro- and macroenvironment. The rediscovery of the presence and activity of brown adipose tissue in adult humans has renewed the interest on adaptive thermogenesis (AT) as a means to facilitate weight loss and improve carbohydrate metabolism. The aim of this review is to describe the recent advancements in the study of this function, and to assess the potential and limitations of exploiting AT for environmental/behavior- al, and pharmacological interventions. Introduction The ability to maintain a constant core temperature, a defining characteristic of homoeothermic animals, pro- vides an evolutionary advantage by allowing the survival and propagation of the species in a wide range of environ- ments. This is assured by the concerted interplay of neu- ronal, hormonal, immunological, and metabolic pathways [1–3]. However, the associated energy costs are consider- able and conflict with the limiting factor for the expansion of virtually all biological systems: energy availability. Thus, an efficient (from the energy conservation perspec- tive) maintenance of core temperature represents the syn- thesis between these two apparently competing objectives. Over the centuries, humans have gained the ability to modify their environment, and seldom face famine; fur- thermore, the energy expenditure (EE) required to gather nourishment has dramatically reduced. The evolutionary pressure toward energy conservation has thus become one of the causes of the obesity epidemic and obesity-related morbidity [4]. AT (see Glossary) has been studied in both animals and humans for over a century (Box 1). The rediscovery of brown adipose tissue (BAT) in adult humans has prompted a renewed interest in the study of AT as a potential target for increasing EE, generating a sustained negative energy balance, and ultimately reversing weight gain. Recently, intensive mechanistic and translational research has shed light on the physiology of human AT, as well on its hor- monal and metabolic effects [5]. As seen in other endocrine axes, BAT is not only the target of hormonal signaling, but has also a secretory activity, thereby closing the signaling loop [6]. This review characterizes the components and physiol- ogy of human AT response, describes the experimental physiology and imaging tools for its assessment, and the signaling and metabolic consequences of AT response. Ultimately, we aim to critically appraise the potential and limitations of AT as a target for environmental, be- havioral, and pharmacological interventions. Definition of AT AT is defined as the complex and coordinated response of homoeothermic organisms to increase the rate of EE above normal baseline levels when exposed to cold. The afferent limb of this response allows for various stimuli to transmit Review Glossary Adaptive thermogenesis (AT): the complex and coordinated response of homoeothermic organisms to increase the rate of EE above normal baseline levels when exposed to cold to maintain core temperature. Capsaicin: the most pungent member of the capsaicinoid family of com- pounds, found in hot red peppers, which can induce increases in EE. Capsinoid: a general term for the compounds capsiate, dihydrocapsiate, and nordihydorcapsiate, all of which are nonpungent capsaicin analogues found in CH-19 sweet pepper. 2,4-dinotrophenol (DNP): is an organic compound and best-known agent for uncoupling oxidative phosphorylation. DNP promotes protons to leak across the inner mitochondrial membrane and the energy that is normally produced from cellular respiration is wasted as heat. Ephedra: herbal products derived from the plant genus Ephedra, which contain ephedrine. Ephedrine: a sympathomimetic amine, with stimulant properties, which is the primary active component of ephedra. FGF21: a member of the fibroblast growth factor family, expressed by several tissues, with multiple endocrine and paracrine effects on glucose and lipid metabolism. Homeothermic: maintaining a constant internal body temperature indepen- dently of the surrounding environmental temperature. Irisin: also known as fibronectin type III domain-containing protein 5 (FDNC5), a peptide hormone secreted by muscle in response to exercise. Mirabegron: a novel b-3 adrenoreceptor agonist. Nonshivering thermogenesis (NST): an increase in heat production not derived from muscle contractions in response to cold, as seen in brown adipose tissue in response to activation of the SNS with cold exposure or food ingestion. Shivering thermogenesis (ST): the generation of heat from skeletal muscle contractions in response to cold. Uncoupling protein 1 (UCP-1): is a transporter protein found in the mitochondria of brown adipose tissue. It induces energy dissipation in the form of heat by creating proton leaks across the inner mitochondrial membrane and thus uncoupling oxidative phosphorylation from ATP synthesis. 1043-2760/ ß 2015 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.tem.2015.03.003 Corresponding author: Celi, F.S. (fsceli@vcu.edu). Keywords: adaptive thermogenesis; brown adipose tissue; humans. TEM-1022; No. of Pages 10 Trends in Endocrinology and Metabolism xx (2015) 1–10 1