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Sunday, June 6, 2010

Brown Fat and the MYTH of Diet-Induced Thermogenesis

Brown Fat and the Myth of Diet-Induced Thermogenesis

INTRODUCTION:  The concept that brown adipose tissue (BAT) is a thermogenic tissue initially came from morphological changes in the tissue when animals were exposed to the cold (Smith and Horwitz, 1969). The physiological basis for the enormous capacity of BAT for heat production during cold exposure awaited the ingenious application of radiolabeled microspheres to measure blood flow in BAT and other tissues (Foster and Frydman, 1978). That production of heat occurred by uncoupling mitochondria was firmly established with the elegant experiments of Nicholls on physiology of BAT mitochondria and Ricquier’s identification of a unique cold-inducible protein in the mitochondria of BAT (Nicholls and Locke, 1984). The presence of large amounts of differentiated BAT in human neonates and species like sheep that require active thermogenesis at birth to protect the newborn from cold exposure on a snow-covered pasture in spring argues that BAT evolved primarily to function as a thermogenic system to protect body temperature (Casteilla et al., 1989).
What is a matter for debate is whether BAT thermogenesis burns off excess calories in a state of positive energy balance o maintain energy homeostasis as a major physiological function.  This concept emerged from experiments in the 1970s when Rothwell and Stock observed that rats fed a cafeteria diet (composed of junk foods high in fats and sugars) gained less weight than expected from caloric intake, and they proposed that excess unaccounted calories were being burned off by the induction of BAT thermogenesis (Rothwell and Stock, 1979).  Accordingly, BAT thermogenesis was proposed as a mechanism not only for protecting body temperature, but also to protect against obesity and the development of insulin resistance.  The data for diet-induced thermogenesis dovetailed with evidence that cold sensitivity and obesity phenotypes in ob/ob mice were associated with defective BAT nonshivering thermogenesis (Trayhurn et al., 1977). This idea that obesity was caused by a defective BAT set in motion a major effort by clinicians to find obese individuals with a slow metabolism. Prentice has commented on the depth of frustration experienced by clinicians when they failed to find obese humans with slow metabolism (Prentice and Jebb, 2004). Prentice blamed research investigating energy expenditure in the ob/ob mouse for this fruitless phase of obesity research in humans, concluding that the fundamental phenotypes of obesity and body weight regulation in ob/ob mice and humans were different. It is now well established that energy expenditure increases as a function of body mass in humans, and accordingly severe obesity is associated with an increase in energy expenditure (Leibel et al., 1995). Moreover, in the interim it became clear that ob/ob mice have neither reduced energy expenditure nor defective BAT per se. Energy expenditure in ob/ob mice was underestimated from the erroneous calculation of energy expenditure in studies comparing lean and obese mice, a problem that persists with a frustratingly high frequency to this day (Butler and Kozak, 2010).  Perceived defects in brown fat did not come from intrinsic defects in Ucp1 induction, but from secondary problems related to excessive white fat in morbidly obese ob/ob mice and regulatory problems arising from downregulation of b1- and b3-adrenergic receptors in ob/ob mice and other models of obesity that attenuate induction of Ucp1 and lipolysis (Robidoux et al., 2004). That none of the phenotypes of energy balance in ob/ob mice are due to modulation of Ucp1 expression was established with experiments showing that phenotypes of energy balance including food intake, adiposity, and oxygen consumption do not vary between ob/ob and Lep / .Ucp / mice under basal and leptin-stimulated conditions (Ukropec et al., 2006). Accordingly, the basic phenotypes relating to energy expenditure and obesity in mouse and human models of leptin null mutations are in agreement (Farooqi et al., 1999), and the data do not implicate BAT.

CONCLUSIONS:  Would it matter to our concepts of energy balance if there was no diet-induced thermogenesis? Probably not, since as I have argued from the phenotypes of several genetic models of thermogenesis, no compelling case can be made for diet-driven thermogenesis. Expenditure of energy to balance food intake would come principally from physical activity and maintenance of body temperature in individuals in harmony with their environment; this would exclude most modern humans.  The realization this past year that significant levels of BAT continue to exist in adult humans has opened the door to research that will aim to determine how this remarkable thermogenic system may be associated with the obesity epidemic and to discover new ways to utilize the potential to expand and activate BAT thermogenesis to prevent or reduce obesity in individuals. Similar excitement about the potential contribution of variation in BAT to slow metabolism and increased susceptibility to obesity occurred 30 years ago. The effort that flowed from this excitement and energy faded because we failed to understand that the function of BAT in mammals is to maintain body temperature in the face of a cold environment and not to maintain a normal body weight free of insulin resistance in the face of an obesogenic environment.

BOTTOM LINE?  The  title of this review says it all.  Those proposing a metabolic advantage for LC diets involving futile cycling of fat have no leg to stand on for that aspect.

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