Comprehensive Physiology Wiley Online Library

Maintaining Thermogenesis in Cold Exposed Humans: Relying on Multiple Metabolic Pathways

Full Article on Wiley Online Library



Abstract

In cold exposed humans, increasing thermogenic rate is essential to prevent decreases in core temperature. This review describes the metabolic requirements of thermogenic pathways, mainly shivering thermogenesis, the largest contributor of heat. Research has shown that thermogenesis is sustained from a combination of carbohydrates, lipids, and proteins. The mixture of fuels is influenced by shivering intensity and pattern as well as by modifications in energy reserves and nutritional status. To date, there are no indications that differences in the types of fuel being used can alter shivering and overall heat production. We also bring forth the potential contribution of nonshivering thermogenesis in adult humans via the activation of brown adipose tissue (BAT) and explore some means to stimulate the activity of this highly thermogenic tissue. Clearly, the potential role of BAT, especially in young lean adults, can no longer be ignored. However, much work remains to clearly identify the quantitative nature of this tissue's contribution to total thermogenic rate and influence on shivering thermogenesis. Identifying ways to potentiate the effects of BAT via cold acclimation and/or the ingestion of compounds that stimulate the thermogenic process may have important implications in cold endurance and survival. © 2014 American Physiological Society. Compr Physiol 4:1383‐1402, 2014.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Anatomical conceptual illustration of neural networks that make up the somatosensory and autonomic thermoregulatory pathways. See Section “Activating thermogenic pathways” for details.
Figure 2. Figure 2. Relative changes in (A) core temperature (Tcore), (B) average shivering intensity of four large muscles [trapezius, latissimus dorsi, pectoralis major, and rectus abdominis expressed in % of maximal voluntary contraction (%MVC)] and C. oxygen consumption (L/min) as a function of the relative change in average skin temperature in men exposed to various cold conditions using an liquid conditioned garment. Values are adapted, with permission, from ().
Figure 3. Figure 3. (A) Absolute rates (mg·min−1) and (B) relative contributions to total thermogenic rate of carbohydrates (CHO, open bars) and lipids (black bars) in men exposed to the cold at various intensities [2.6, 3.5, or 4.7 times resting metabolic rate (X RMR)], following the ingestion of glucose and/or fructose at different rates and times as, well as following the depletion or loading of CHO reserves. Values are adapted, with permission, from ().
Figure 4. Figure 4. Interindividual differences in burst shivering rate and its effect on total CHO, muscle glycogen, and plasma glucose utilization. Values are adapted, with permission, from ().
Figure 5. Figure 5. (A) Absolute rates (mg·min−1) and (B) relative contributions to total thermogenic rate of muscle glycogen (open bars) and plasma glucose (black bars) in men exposed to the cold at various intensities [2.6 and 3.5 times resting metabolic rate (X RMR)], following the ingestion of glucose alone or with fructose at different rates and times as, well as following the depletion or loading of CHO reserves. Values are adapted, with permission, from ().


Figure 1. Anatomical conceptual illustration of neural networks that make up the somatosensory and autonomic thermoregulatory pathways. See Section “Activating thermogenic pathways” for details.


Figure 2. Relative changes in (A) core temperature (Tcore), (B) average shivering intensity of four large muscles [trapezius, latissimus dorsi, pectoralis major, and rectus abdominis expressed in % of maximal voluntary contraction (%MVC)] and C. oxygen consumption (L/min) as a function of the relative change in average skin temperature in men exposed to various cold conditions using an liquid conditioned garment. Values are adapted, with permission, from ().


Figure 3. (A) Absolute rates (mg·min−1) and (B) relative contributions to total thermogenic rate of carbohydrates (CHO, open bars) and lipids (black bars) in men exposed to the cold at various intensities [2.6, 3.5, or 4.7 times resting metabolic rate (X RMR)], following the ingestion of glucose and/or fructose at different rates and times as, well as following the depletion or loading of CHO reserves. Values are adapted, with permission, from ().


Figure 4. Interindividual differences in burst shivering rate and its effect on total CHO, muscle glycogen, and plasma glucose utilization. Values are adapted, with permission, from ().


Figure 5. (A) Absolute rates (mg·min−1) and (B) relative contributions to total thermogenic rate of muscle glycogen (open bars) and plasma glucose (black bars) in men exposed to the cold at various intensities [2.6 and 3.5 times resting metabolic rate (X RMR)], following the ingestion of glucose alone or with fructose at different rates and times as, well as following the depletion or loading of CHO reserves. Values are adapted, with permission, from ().
References
 1.Achten J, Gleeson M, Jeukendrup AE. Determination of the exercise intensity that elicits maximal fat oxidation. Med Sci Sports Exerc 34: 92‐97, 2002.
 2.Astrup A, Bulow J, Madsen J, Christensen NJ. Contribution of BAT and skeletal muscle to thermogenesis induced by ephedrine in man. Am J Physiol 248: E507‐E515, 1985.
 3.Astrup A, Toubro S, Cannon S, Hein P, Madsen J. Thermogenic synergism between ephedrine and caffeine in healthy volunteers: A double‐blind, placebo‐controlled study. Metabolism 40: 323‐329, 1991.
 4.Aydin J, Shabalina IG, Place N, Reiken S, Zhang SJ, Bellinger AM, Nedergaard J, Cannon B, Marks AR, Bruton JD, Westerblad H. Nonshivering thermogenesis protects against defective calcium handling in muscle. FASEB J 22: 3919‐3924, 2008.
 5.Bae KA, An NY, Kwon YW, Kim C, Yoon CS, Park SC, Kim CK. Muscle fibre size and capillarity in Korean diving women. Acta Physiol Scand 179: 167‐172, 2003.
 6.Barre H, Geloen A, Chatonnet J, Dittmar A, Rouanet JL. Potentiated muscular thermogenesis in cold‐acclimated muscovy duckling. Am J Physiol 249: R533‐R538, 1985.
 7.Beavers WR, Covino BG. Effects of oral glycine during cold exposure in man. J Appl Physiol 14: 390‐392, 1959.
 8.Beckman EL, Reeves E. Physiological implications as to survival during immersion in water at 75 degrees F. Aerosp Med. 37: 1136‐1142, 1966.
 9.Bell DG, Tikuisis P, Jacobs I. Relative intensity of muscular contraction during shivering. J Appl Physiol 72: 2336‐2342, 1992.
 10.Bishop CM. The maximum oxygen consumption and aerobic scope of birds and mammals: Getting to the heart of the matter. Proc Biol Sci 266: 2275‐2281, 1999.
 11.Bittel JH. Heat debt as an index for cold adaptation in men. J Appl Physiol 62: 1627‐1634, 1987.
 12.Blondin DP, Dépault I, Imbeault P, Péronnet F, Imbeault M‐A, Haman F. Effects of two glucose ingestion rates on substrate utilization during moderate‐intensity shivering. Eur J Appl Physiol 108: 289‐300, 2010.
 13.Blondin DP, Labbé SM, Tingelstad HC, Noll C, Kunach M, Phoenix S, Guérin B, Turcotte ÉE, Carpentier AC, Richard D, Haman F. Increased brown adipose tissue oxidative capacity in cold‐acclimated humans. J Clin Endocrinol Metab 99: E438‐E446, 2014.
 14.Blondin DP, Maneshi A, Imbeault MA, Haman F. Effects of the menstrual cycle on muscle recruitment and oxidative fuel selection during cold exposure. J Appl Physiol 111: 1014‐1020, 2011.
 15.Blondin DP, Peronnet F, Haman F. Effects of ingesting [13C]glucose early or late into cold exposure on substrate utilization. J Appl Physiol 109: 654‐662, 2010.
 16.Blondin DP, Peronnet F, Haman F. Coingesting glucose and fructose in the cold potentiates exogenous CHO oxidation. Med Sci Sports Exerc 44: 1706‐1714, 2012.
 17.Borchardt RT, Huber JA. Catechol O‐methyltransferase. 5. Structure‐activity relationships for inhibition by flavonoids. J Med Chem 18: 120‐122, 1975.
 18.Burton A, Bazett J. A study of the average temperature of the tissues, of exchanges of heat, and vasomotor responses in man by means of a bath calorimeter. Am J Physiol 117: 36, 1936.
 19.Campero M, Serra J, Bostock H, Ochoa JL. Slowly conducting afferents activated by innocuous low temperature in human skin. J Physiol 535: 855‐865, 2001.
 20.Cannon B, Nedergaard J. Brown adipose tissue: Function and physiological significance. Physiol Rev 84: 277‐359, 2004.
 21.Carey AL, Formosa MF, Van Every B, Bertovic D, Eikelis N, Lambert GW, Kalff V, Duffy SJ, Cherk MH, Kingwell BA. Ephedrine activates brown adipose tissue in lean but not obese humans. Diabetologia 56: 147‐155, 2013.
 22.Carlson M, Snead W, Campbell P. Fuel and energy metabolism in fasting humans. Am J Clin Nutr 60: 29‐36, 1994.
 23.Casazza GA, Jacobs KA, Suh SH, Miller BF, Horning MA, Brooks GA. Menstrual cycle phase and oral contraceptive effects on triglyceride mobilization during exercise. J Appl Physiol 97: 302‐309, 2004.
 24.Casey KL, Minoshima S, Morrow TJ, Koeppe RA. Comparison of human cerebral activation pattern during cutaneous warmth, heat pain, and deep cold pain. J Neurophysiol 76: 571‐581, 1996.
 25.Castellani JW, Stulz DA, Degroot DW, Blanchard LA, Cadarette BS, Nindl BC, Montain SJ. Eighty‐four hours of sustained operations alter thermoregulation during cold exposure. Med Sci Sports Exerc 35: 175‐181, 2003.
 26.Chaffee RR, Roberts JC, Conaway CH, Sorenson MW. Comparative effects of temperature exposure on mass and oxidative enzyme activity of brown fat in insectivores, tupaiads and primates. Lipids 5: 23‐29, 1970.
 27.Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, Shelton JM, Wu H, Zhu W, Bassel‐Duby R, Williams RS. A calcineurin‐dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev 12: 2499‐2509, 1998.
 28.Commission IT. Glossary of terms for thermal physiology. Second edition. Revised by The Commission for Thermal Physiology of the International Union of Physiological Sciences (IUPS Thermal Commission). Japanese J Physiol 51: 245‐280, 2001.
 29.Cypess AM, Chen YC, Sze C, Wang K, English J, Chan O, Holman AR, Tal I, Palmer MR, Kolodny GM, Kahn CR. Cold but not sympathomimetics activates human brown adipose tissue in vivo. Proc Natl Acad Sci U S A 109: 10001‐10005, 2012.
 30.Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360: 1509‐1517, 2009.
 31.Darian‐Smith I, Johnson KO, Dykes R. “Cold” fiber population innervating palmar and digital skin of the monkey: Responses to cooling pulses. J Neurophysiol 36: 325‐346, 1973.
 32.Davis KD, Kwan CL, Crawley AP, Mikulis DJ. Functional MRI study of thalamic and cortical activations evoked by cutaneous heat, cold, and tactile stimuli. J Neurophysiol 80: 1533‐1546, 1998.
 33.Davis TRA. Chamber cold acclimatization in man. J Appl Physiol 16: 1011‐1015, 1961.
 34.Dulloo AG, Seydoux J, Girardier L, Chantre P, Vandermander J. Green tea and thermogenesis: Interactions between catechin‐polyphenols, caffeine and sympathetic activity. Int J Obes Relat Metab Disord 24: 252‐258, 2000.
 35.Egan GF, Johnson J, Farrell M, McAllen R, Zamarripa F, McKinley MJ, Lancaster J, Denton D, Fox PT. Cortical, thalamic, and hypothalamic responses to cooling and warming the skin in awake humans: A positron‐emission tomography study. Proc Natl Acad Sci U S A 102: 5262‐5267, 2005.
 36.Elsner RW, Andersen KL, Hermansen L. Thermal and metabolic responses of Arctic Indians to moderate cold exposure at the end of winter. J Appl Physiol 15: 659‐661, 1960.
 37.Eyolfson DA, Tikuisis P, Xu X, Weseen G, Giesbrecht GG. Measurement and prediction of peak shivering intensity in humans. Eur J Appl Physiol 84: 100‐106, 2001.
 38.Frayn KN. Metabolic Regulation: A Human Perspective. Malden, MA: Blackwell, 2003.
 39.Gale EA, Bennett T, Green JH, MacDonald IA. Hypoglycaemia, hypothermia and shivering in man. Clin Sci (Lond) 61: 463‐469, 1981.
 40.Gardiner P. Neuromuscular Aspects of Physical Activity. Windsor, ON, Canada: Human Kinetics, 2001.
 41.Gessner K. Conradi Gesneri medici Trigurine Historae Animalium: Lib. I De Quadredibus viviparis. 1551.
 42.Glickman‐Weiss E, Caine N, Cheatham CC, Blegen M, Scharschmidt T, Marcinkiewicz J. The effects of gender and menstrual phase on carbohydrate utilization during acute cold exposure. Wilderness Env Med 11: 5‐11, 2000.
 43.Glickman‐Weiss EL, Nelson AG, Hearon CM, Vasanthakumar SR, Stringer BT. Does feeding regime affect physiologic and thermal responses during exposure to 8, 20, and 27°C? Eur J Appl Physiol 67: 30‐34, 1993.
 44.Glickman‐Weiss EL, Nelson AG, Hearon CM, Windhauser M, Heltz D. The thermogenic effect of carbohydrate feeding during exposure to 8, 12 and 27°C. Eur J Appl Physiol 68: 291‐297, 1994.
 45.Gosselin C, Haman F. Effects of green tea extracts on non‐shivering thermogenesis during mild cold exposure in young men. Br J Nutr 110: 282‐288, 2013.
 46.Graham TE, Sathasivam P, MacNaughton KW. Influence of cold, exercise, and caffeine on catecholamines and metabolism in men. J Appl Physiol (1985) 70: 2052‐2058, 1991.
 47.Grenier‐Larouche T, Labbe SM, Noll C, Richard D, Carpentier AC. Metabolic inflexibility of white and brown adipose tissues in abnormal fatty acid partitioning of type 2 diabetes. Int J Obes Supp 2: S37‐S42, 2012.
 48.Hackney AC, McCracken‐Compton MA, Ainsworth B. Substrate responses to submaximal exercise in the midfollicular and midluteal phases of the menstrual cycle. . Int J Sport Nutr 4: 299‐308, 1994.
 49.Haight JS, Keatinge WR. Failure of thermoregulation in the cold during hypoglycaemia induced by exercise and ethanol. J Physiol 229: 87‐97, 1973.
 50.Haman F. Shivering in the cold: From mechanisms of fuel selection to survival. J Appl Physiol 100: 1702‐1708, 2006.
 51.Haman F, Blondin DP, Imbeault MA, Maneshi A. Metabolic requirements of shivering humans. Front Biosci (Schol Ed) 2: 1155‐1168, 2010.
 52.Haman F, Legault SR, Rakobowchuk M, Ducharme MB, Weber J‐M. Effects of carbohydrate availability on sustained shivering II: Relating muscle recruitment to fuel selection. J Appl Physiol 96: 41‐49, 2004.
 53.Haman F, Legault SR, Weber JM. Fuel selection during intense shivering in humans: EMG pattern reflects carbohydrate oxidation. J Physiol 556: 305‐313, 2004.
 54.Haman F, Peronnet F, Kenny GP, Doucet E, Massicotte D, Lavoie C, Weber JM. Effects of carbohydrate availability on sustained shivering I. Oxidation of plasma glucose, muscle glycogen, and proteins. J Appl Physiol 96: 32‐40, 2004.
 55.Haman F, Péronnet F, Kenny GP, Massicotte D, Lavoie C, Scott C, Weber J‐M. Effect of cold exposure on fuel utilization in humans: Plasma glucose, muscle glycogen, and lipids. J Appl Physiol 93: 77‐84, 2002.
 56.Haman F, Péronnet F, Kenny GP, Massicotte D, Lavoie C, Weber J‐M. Partitioning oxidative fuels during cold exposure in humans: Muscle glycogen becomes dominant as shivering intensifies. J Physiol 566: 247‐256, 2005.
 57.Haman F, Scott CG, Kenny GP. Fueling shivering thermogenesis during passive hypothermic recovery. J Appl Physiol 103: 1346‐1351, 2007.
 58.Hammel HT, Elsner RW, Le Messurier DH, Andersen HT, Milan FA. Thermal and metabolic responses of the Australian aborigine exposed to moderate cold in summer. J Appl Physiol 14: 605‐615, 1959.
 59.Hart JS, Heroux O, Depocas F. Cold acclimation and the electromyogram of unanesthetized rats. J Appl Physiol 9: 404‐408, 1956.
 60.Hart JS, Sabean HB, Hildes JA, Depocas F, Hammel HT, Andersen KL, Irving L, Foy G. Thermal and metabolic responses of coastal Eskimos during a cold night. J Appl Physiol 17: 953‐960, 1962.
 61.Heaton JM. The distribution of brown adipose tissue in the human. J Anat 112: 35‐39, 1972.
 62.Hesslink RLJ, D'Alesandro MM, Armstrong DWr, Reed HL. Human cold air habituation is independent of thyroxine and thyrotropin. J Appl Physiol 72: 2134‐2139, 1992.
 63.Hilliges M, Wang L, Johansson O. Ultrastructural evidence for nerve fibers within all vital layers of the human epidermis. J Invest Dermatol 104: 134‐137, 1995.
 64.Hohtola E, Henderson RP, Rashotte ME. Shivering thermogenesis in the pigeon: The effects of activity, diurnal factors, and feeding state. Am J Physiol 275: R1553‐R1562, 1998.
 65.Hong SK, Rahn H, Kang DH, Song SH, Kang BS. Diving pattern, lung volumes, and alveolar gas of the Korean diving woman (ama). J Appl Physiol 18: 457‐465, 1963.
 66.Horton TJ, Miller EK, Glueck D, Tench K. No effect of menstrual cycle phase on glucose kinetics and fuel oxidation during moderate‐intensity exercise. Am J Physiol Endocrinol Metab 282: E752‐E762, 2002.
 67.Huttunen P, Hirvonen J, Kinnula V. The occurrence of brown adipose tissue in outdoor workers. Eur J Appl Physiol Occup Physiol 46: 339‐345, 1981.
 68.Imbeault M‐A, Mantha OL, Haman F. Shivering modulation in humans: Effects of rapid changes in environmental temperature. J Therm Biol 38: 582‐587, 2013.
 69.Israel DJ, Pozos RS. Synchronized slow‐amplitude modulations in the electromyograms of shivering muscles. J Appl Physiol 66: 2358‐2363, 1989.
 70.Jeukendrup AE. Regulation of fat metabolism in skeletal muscle. Ann NY Acad Sci 967: 217‐235, 2002.
 71.Jones P, Lee I. Macronutrient requirements for work in cold environments. In: Marriott B, Carlson S, editors. Nutrional Needs in Cold and In High‐Altitude Environments: Applications for Military Personnel in Field Operations. Washington, D.C.: National Academy Press, 1996, pp. 189‐202.
 72.Kang BS, Song SH, Suh CS, Hong SK. Changes in body temperature and basal metabolic rate of the ama. J Appl Physiol 18: 483‐488, 1963.
 73.Kanosue K, Sadato N, Okada T, Yoda T, Nakai S, Yoshida K, Hosono T, Nagashima K, Yagishita T, Inoue O, Kobayashi K, Yonekura Y. Brain activation during whole body cooling in humans studied with functional magnetic resonance imaging. Neurosci Lett 329: 157‐160, 2002.
 74.Klein LJ, Visser FC, Knaapen P, Peters JH, Teule GJ, Visser CA, Lammertsma AA. Carbon‐11 acetate as a tracer of myocardial oxygen consumption. Eur J Nucl Med 28: 651‐668, 2001.
 75.Kobayashi A, Osaka T, Namba Y, Inoue S, Lee TH, Kimura S. Capsaicin activates heat loss and heat production simultaneously and independently in rats. Am J Physiol 275: R92‐R98, 1998.
 76.Kowalczyk M, Antkowiak B, Antkowiak O, Brytan M, Zdanowski R, Klos A, Frankiewicz‐Jozko A. Ephedrine‐caffeine mixture in wet‐cold stress. Pharmacol Rep 58: 364‐372, 2006.
 77.Macdonald I, Bennett T, Sainsbury R. The effect of a 48h fast on the thermoregulatory responses to graded cooling in man. Clin Sci 67: 445‐452, 1984.
 78.MacNaughton KW, Sathasivam P, Vallerand AL, Graham TE. Influence of caffeine on metabolic responses of men at rest in 28 and 5 degrees C. J Appl Physiol 68: 1889‐1895, 1990.
 79.Mansell P, Fellows I, Macdonald I. Enhanced thermogenic response to epinephrine after 48‐h starvation in humans. Am J Physiol Regul Integr Comp Physiol 258: 87‐93, 1990.
 80.Mansell P, Macdonald I. Effects of underfeeding and of starvation on thermoregulatory responses to cooling in women. Clin Sci 77: 245‐252, 1989.
 81.Martineau L, Jacobs I. Free fatty acid availability and temperature regulation in cold water. J Appl Physiol 67: 2466‐2472, 1989.
 82.Martineau L, Jacobs I. Muscle glycogen availability and temperature regulation in humans. J Appl Physiol 66: 72‐78, 1989.
 83.Martineau L, Jacobs I. Effects of muscle glycogen and plasma FFA availability on human metabolism responses in cold water. J Appl Physiol 71: 1331‐1339, 1991.
 84.McAllen RM, Farrell M, Johnson JM, Trevaks D, Cole L, McKinley MJ, Jackson G, Denton DA, Egan GF. Human medullary responses to cooling and rewarming the skin: A functional MRI study. Proc Natl Acad Sci U S A 103: 809‐813, 2006.
 85.McAllen RM, Tanaka M, Ootsuka Y, McKinley MJ. Multiple thermoregulatory effectors with independent central controls. Eur J Appl Physiol 109: 27‐33, 2010.
 86.Meigal A. Gross and fine neuromuscular performance at cold shivering. Int J Circumpolar Health 61: 163‐172, 2002.
 87.Meigal A, Lupandin V, Kuzmina GI. Electromyographic patterns of thermoregulatory activity of motor units in the course of body cooling. Fiziol Cheloveka 19: 106‐114 (in Russian), 1993.
 88.Morrison SF. 2010 Carl Ludwig Distinguished Lectureship of the APS Neural Control and Autonomic Regulation Section: Central neural pathways for thermoregulatory cold defense. J Appl Physiol 110: 1137‐1149, 2011.
 89.Nakamura K. Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol 301: R1207‐R1228, 2011.
 90.Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 293: E444‐E452, 2007.
 91.Olson JM. The ontogeny of shivering thermogenesis in the red‐winged blackbird (agelaius phoeniceus). J Exp Biol 191: 59‐88, 1994.
 92.Orava J, Nuutila P, Noponen T, Parkkola R, Viljanen T, Enerback S, Rissanen A, Pietilainen KH, Virtanen KA. Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans. Obesity (Silver Spring) 12: 2279‐2287, 2013.
 93.Ouellet V, Labbe SM, Blondin DP, Phoenix S, Guerin B, Haman F, Turcotte EE, Richard D, Carpentier AC. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin invest 122: 545‐552, 2012.
 94.Ouellet V, Routhier‐Labadie A, Bellemare W, Lakhal‐Chaieb L, Turcotte E, Carpentier AC, Richard D. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose‐uptake activity of 18F‐FDG‐detected BAT in Humans. J Clin Endocrinol Metab 96: 192‐199, 2011.
 95.Park Y, Pendergast D, Rennie D. Decrease in body insulation with exercise in cool water. Undersea Biomed Res 11: 159‐168, 1984.
 96.Passias TC, Meneilly GS, Mekjavic IB. Effect of hypoglycemia on thermoregulatory responses. J Appl Physiol 80: 1021‐1032, 1996.
 97.Pirnay F, Crielaard JM, Pallikarakis N, Lacroix M, Mosora F, Krzentowski G, Luyckx AS, Lefebvre PJ. Fate of exogenous glucose during exercise of different intensities in humans. J Appl Physiol 53: 1620‐1624, 1982.
 98.Pohl H. Temperature regulation and cold acclimation in the golden hamster. J Appl Physiol 20: 405‐410, 1965.
 99.Rattigan S, Wheatley C, Richards SM, Barrett EJ, Clark MG. Exercise and Insulin‐mediated capillary recruitment in muscle. Exerc Sport Sci Rev 33: 43‐48, 2005.
 100.Rennie D. Tissue heat transfer in water: Lessons from the Korean divers. Med Sci Sports Exerc 20: S177‐S184, 1988.
 101.Rezende EL, Swanson DL, Novoa FF, Bozinovic F. Passerines versus nonpasserines: So far, no statistical differences in the scaling of avian energetics. J Exp Biol 205: 101‐107, 2002.
 102.Richter EA, Hargreaves M. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol Rev 93: 993‐1017, 2013.
 103.Rochelle R, Horvath S. Metabolic responses to food and acute cold stress. J Appl Physiol 27: 710‐714, 1969.
 104.Rolfe DFS, Brown GC. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev 77: 731‐758, 1997.
 105.Romanovsky AA. Thermoregulation: Some concepts have changed. Functional architecture of the thermoregulatory system. Am J Physiol Regul Integr Comp Physiol 292: R37‐R46, 2007.
 106.Saito M, Okamatsu‐Ogura Y, Matsushita M, Watanbe K, Yoneshiro T, Nio‐Kobayashi J, Iwanaga I, Miyagawa M, Kameya T, Nakada K, Kawai Y, Tsujisaki M. High incidence of metabolically active brown adipose tissue in healthy adult humans. Diabetes 58: 1526‐1531, 2009.
 107.Sato H. Fusimotor modulation by spinal and skin temperature changes and its significance in cold shivering. Exp Neurol 74: 21‐32, 1981.
 108.Sato H, Hashitani T, Isobe Y, Furuyama F, Nishino H. Descending influences from nucleus raphe magnus on fusimotor neurone activity in rats. J Therm Biol 15: 259‐265, 1990.
 109.Schepers RJ, Ringkamp M. Thermoreceptors and thermosensitive afferents. Neurosci Biobehav Rev 34: 177‐184, 2010.
 110.Schmidt‐Nielsen K. Scaling: Why is Animal Size So Important? Cambridge, UK: Cambridge University Press, 1984.
 111.Scott E. Nutrition of Alaskan Eskimos. Nutri Rev 14: 1‐3, 1956.
 112.Shixian Q, VanCrey B, Shi J, Kakuda Y, Jiang Y. Green tea extract thermogenesis‐induced weight loss by epigallocatechin gallate inhibition of catechol‐O‐methyltransferase. J Med Food 9: 451‐458, 2006.
 113.Simoneau JA, Bouchard C. Human variation in skeletal muscle fiber‐type proportion and enzyme activities. Am J Physiol 257: E567‐E572, 1989.
 114.Simonides WS, Thelen MH, van der Linden CG, Muller A, van Hardeveld C. Mechanism of thyroid‐hormone regulated expression of the SERCA genes in skeletal muscle: Implications for thermogenesis. Biosci Rep 21: 139‐154, 2001.
 115.Sinclair H. The diet of Canadian Indians and Eskimos. Proc Nutr Soc 12: 69‐82, 1953.
 116.Soderlund V, Larsson SA, Jacobsson H. Reduction of FDG uptake in brown adipose tissue in clinical patients by a single dose of propranolol. Eur J Nucl Med Mol Imaging 34: 1018‐1022, 2007.
 117.Spriet LL. Regulation of skeletal muscle fat oxidation during exercise in humans. Med Sci Sports Exerc 34: 1477–1484, 2002.
 118.Tanaka M, Owens NC, Nagashima K, Kanosue K, McAllen RM. Reflex activation of rat fusimotor neurons by body surface cooling, and its dependence on the medullary raphe. J Physiol 572: 569‐583, 2006.
 119.Tappy L. Thermic effect of food and sympathetic nervous system activity in humans. Reprod Nutr Dev 36: 391‐397, 1996.
 120.Tarnopolsky MA. Sex differences in exercise metabolism and the role of 17‐beta estradiol. Med Sci Sports Exerc 40: 648‐654, 2008.
 121.Teulier L, Rouanet JL, Letexier D, Romestaing C, Belouze M, Rey B, Duchamp C, Roussel D. Cold‐acclimation‐induced non‐shivering thermogenesis in birds is associated with upregulation of avian UCP but not with innate uncoupling or altered ATP efficiency. J Exp Biol 213: 2476‐2482, 2010.
 122.Tikuisis P, Eyolfson DA, Xu X, Giesbrecht GG. Shivering endurance and fatigue during cold water immersion in humans. Eur J Appl Physiol 87: 50‐58, 2002.
 123.Tikuisis P, Giesbrecht GG. Prediction of shivering heat production from core and mean skin temperatures. Eur J Appl Physiol Occup Physiol 79: 221‐229, 1999.
 124.Vallerand AL. Effects of ephedrine/xanthines on thermogenesis and cold tolerance. Int J Obes Relat Metab Disord 17 Suppl 1: S53‐S56, 1993.
 125.Vallerand AL, Frim J, Kavanagh F. Plasma glucose and insulin responses to oral and intravenous glucose in cold‐exposed humans. J Appl Physiol 65: 2395‐2399, 1988.
 126.Vallerand AL, Jacobs I. Energy metabolism during cold exposure. Int J Sports Med 13: S191‐S193, 1992.
 127.Vallerand AL, Jacobs I, Kavanagh MF. Mechanism of enhanced cold tolerance by an ephedrine‐caffeine mixture in humans. J Appl Physiol 67: 438‐444, 1989.
 128.Vallerand AL, Schmegner IF, Jacobs I. Influence of the Cold Buster™ sports bar on heat debt, mobilization and oxidation of energy substrates: Department of National Defence: Defence and Civil Institute of Environmental Medicine. North York, Ontario. Report 92‐60, 1992.
 129.Vallerand AL, Tikuisis P, Ducharme MB, Jacobs I. Is energy substrate mobilization a limiting factor for cold thermogenesis? Eur J Appl Physiol 67: 239‐244, 1993.
 130.Vallerand AL, Wang LCH, Jacobs I. Influence of theobromine on heat production and body temperatures in cold‐exposed humans: A preliminary report, edited by Department of National Defence: Defence and Civil Institute of Environmental Medicine. North York OR‐R‐. North York, Ontario, Canada, 1989.
 131.Vallerand AL, Zamecnik J, Jones PJ, Jacobs I. Cold stress increases lipolysis, FFA Ra and TG/FFA cycling in humans. Aviat Space Environ Med 70: 42‐50, 1999.
 132.van der Lans AA, Hoeks J, Brans B, Vijgen GH, Visser MG, Vosselman MJ, Hansen J, Jorgensen JA, Wu J, Mottaghy FM, Schrauwen P, van Marken Lichtenbelt WD. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest 123: 3395‐3403, 2013.
 133.van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold‐activated brown adipose tissue in health men. N Engl J Med 360: 1500‐1508, 2009.
 134.Veicsteinas A, Ferretti G, Rennie DW. Superficial shell insulation in resting and exercising men in cold water. J Appl Physiol Respir Environ Exerc Physiol 52: 1557‐1564, 1982.
 135.Vijgen GH, Bouvy ND, Teule GJ, Brans B, Hoeks J, Schrauwen P, van Marken Lichtenbelt WD. Increase in brown adipose tissue activity after weight loss in morbidly obese subjects. J Clin Endocrinol Metab 97: E1229‐E1233, 2012.
 136.Vijgen GH, Bouvy ND, Teule GJ, Brans B, Schrauwen P, van Marken Lichtenbelt WD. Brown adipose tissue in morbidly obese subjects. PLoS One 6: e17247, 2011.
 137.Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerback S, Nuutila P. Functional brown adipose tissue in healthy adults. N Engl J Med 360: 1518‐1525, 2009.
 138.Vosselman MJ, van der Lans AA, Brans B, Wierts R, van Baak MA, Schrauwen P, van Marken Lichtenbelt WD. Systemic beta‐adrenergic stimulation of thermogenesis is not accompanied by brown adipose tissue activity in humans. Diabetes 61: 3106‐3113, 2012.
 139.Wang L, Hilliges M, Jernberg T, Wiegleb‐Edstrom D, Johansson O. Protein gene product 9.5‐immunoreactive nerve fibres and cells in human skin. Cell Tissue Res 261: 25‐33, 1990.
 140.Wang LCH, Man SFP, Belcastro A. Improving cold tolerance in men: Effects of substrates and aminophylline. In: Lomax P, Schonbaum E, Cooper K, Veale W, editors. Homeostasis and Thermal Stress: Experimental and Therapeutic Advances. Basel, Switzerland: Karger, 1986, pp. 22‐26.
 141.Webber J, Macdonald I. The cardiovascular, metabolic and hormonal changes accompanying acute starvation in men and women. Br J Nutr 71: 437‐447, 1994.
 142.Weber J‐M, Haman F. Oxidative fuel selection: Adjusting mix and flux to stay alive. In: Morris S, Vosloo A, editors. Animals and Environments. Elsevier, 2004, pp. 22‐31.
 143.Weber JM, Haman F. Fuel selection in shivering humans. Acta Physiol Scand 184: 319‐329, 2005.
 144.Wells JC, Stock JT. The biology of the colonizing ape. Am J Phys Anthropol Suppl 45: 191‐222, 2007.
 145.Wenz M, Berend JZ, Lynch NA, Chappell S, Hackney AC. Substrate oxidation at rest and during exercise: Effects of menstrual cycle phase and diet composition. J Physiol Pharmacol 48: 851‐860, 1997.
 146.Westerterp‐Plantenga M, Diepvens K, Joosen AM, Berube‐Parent S, Tremblay A. Metabolic effects of spices, teas, and caffeine. Physiol Behav 89: 85‐91, 2006.
 147.Wijers SL, Schrauwen P, Saris WH, van Marken Lichtenbelt WD. Human skeletal muscle mitochondrial uncoupling is associated with cold induced adaptive thermogenesis. PLoS ONE 3: e1777, 2008.
 148.Wissler EH. Mathematical simulation of human thermal behavior using whole‐body models. In: Shitzer A, Eberhart RC, editors. Heat Transfer in Medicine and Biology. New York: Plenum Press, 1985, pp. 347‐355.
 149.Xu X, Tikuisis P, Gonzalez R, Giesbrecht G. Thermoregulatory model for prediction of long‐term cold exposure. Comput Biol Med 35: 287‐298, 2005.
 150.Yoneshiro T, Aita S, Kawai Y, Iwanaga T, Saito M. Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans. Am J Clin Nutr 95: 845‐820, 2012.
 151.Yoneshiro T, Aita S, Matsushita M, Kameya T, Nakada K, Kawai Y, Saito M. Brown adipose tissue, whole‐body energy expenditure, and thermogenesis in healthy adult men. Obesity (Silver Spring) 19: 13‐16, 2011.
 152.Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T, Saito M. Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 123: 3404‐3408, 2013.
 153.Young AJ. Homeostatic responses to prolonged cold exposure: Human cold acclimatization. In: Fregly MJ, Blatteis CM, editors. Comprehensive Physiology Supplement 14: Handbook of Physiology, John Wiley & Sons, Inc., pp. 419‐438, 2011.
 154.Young AJ, Castellani JW, O'Brien C, Shippee RL, Tikuisis P, Meyer LG, Blanchard LA, Kain JE, Cadarette BS, Sawka MN. Exertional fatigue, sleep loss, and negative energy balance increase susceptibility to hypothermia. J Appl Physiol 85: 1210‐1217, 1998.
 155.Young AJ, Muza SR, Sawka MN, Gonzalez RR, Pandolf KB. Human thermoregulatory responses to cold air are altered by repeated cold water immersion. J Appl Physiol 60: 1542‐1548, 1986.
 156.Young AJ, Sawka MN, Neufer PD, Muza SR, Askew EW, Pandolf KB. Thermoregulation during cold water immersion is impaired by low glycogen levels. J Appl Physiol 66: 1806‐1816, 1989.
 157.Zderic TW, Coggan AR, Ruby BC. Glucose kinetics and substrate oxidation during exercise in the follicular and luteal phases. J Appl Physiol 90: 447‐453, 2001.
 158.Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, Nedergaard J, Cinti S. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 23: 3113‐3120, 2009.

Related Articles:

Homeostatic Responses to Prolonged Cold Exposure: Human Cold Acclimatization

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Denis P. Blondin, Hans Christian Tingelstad, Olivier L. Mantha, Chantal Gosselin, François Haman. Maintaining Thermogenesis in Cold Exposed Humans: Relying on Multiple Metabolic Pathways. Compr Physiol 2014, 4: 1383-1402. doi: 10.1002/cphy.c130043