Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue i...

Brown Adipose Tissue: Function and Physiological Significance

The assimilation, storage and use of energy from nutrients constitute a homeostatic system that is essential for life In vertebrates, the ability to store sufficient quantities of energy-dense triglyceride in adipose tissue allows survival during the frequent periods of food deprivation encountered during evolution However, the presence of excess adipose tissue can be maladaptive A complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level Leptin, a hormone secreted by adipose tissue, and its receptor are integral components of this system Leptin also signals nutritional status to several other physiological systems and modulates their function Here we review the role of leptin in the control of body weight and its relevance to the pathogenesis of obesity

Leptin and the regulation of body weight in mammals

Background Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. Methods We analyzed 3640 consecutive 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomographic and computed tomographic (PET–CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of 18F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from t...

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Identification and Importance of Brown Adipose Tissue in Adult Humans

https://mootha.med.harvard.edu/PubPDFs/Wu1999.pdf

Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1

Investigations of biological programs that are controlled by gene transcription have mainly studied the regulation of transcription factors. However, there are examples in which the primary focus of biological regulation is at the level of a transcriptional coactivator. We have reviewed here the molecular mechanisms and biological programs controlled by the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha). Key cellular signals that control energy and nutrient homeostasis, such as cAMP and cytokine pathways, strongly activate PGC-1 alpha. Once PGC-1 alpha is activated, it powerfully induces and coordinates gene expression that stimulates mitochondrial oxidative metabolism in brown fat, fiber-type switching in skeletal muscle, and multiple aspects of the fasted response in liver. The regulation of these metabolic and cell fate decisions by PGC-1 alpha is achieved through specific interaction with a variety of transcription factors such as nuclear hormone receptors, nuclear respiratory factors, and muscle-specific transcription factors. PGC-1 alpha therefore constitutes one of the first and clearest examples in which biological programs are chiefly regulated by a transcriptional coactivator in response to environmental stimuli. Finally, PGC-1 alpha's control of energy homeostasis suggests that it could be a target for anti-obesity or diabetes drugs.

Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator.

Measurement of energy balance during voluntary overeating in rats unequivocally establishes the quantitative importance of diet-induced thermogenesis in energy balance. Like cold-induced thermogenesis, this form of heat production involves changes in the activity of the sympathetic nervous system and brown adipose tissue which suggest that this tissue may determine metabolic efficiency and resistance to obesity.

A role for brown adipose tissue in diet-induced thermogenesis

https://onlinelibrary.wiley.com/doi/pdf/10.1002/j.1550-8528.1997.tb00591.x

Brown adipose tissue (BAT) is an important site of adaptive changes in thermogenesis in the rat The sympathetic nervous system, which richly supplies BAT, is thought to play an important role in the regulation of BAT thermogenesis because catecholamines stimulate and beta adrenergic blocking agents inhibit oxygen consumption in this tissue The present studies were carried out to assess directly sympathetic activity in BAT in response to cold exposure and to changes in dietary intake, both of which alter heat production in the rat Sympathetic activity was determined from the rate of norepinephrine (NE) turnover in interscapular brown adipose tissue (IBAT) after preliminary experiments validated the use of NE turnover techniques in IBAT Acute exposure to 4 degrees C increased NE turnover in IBAT 4- to 12-fold compared with ambient temperature controls, depending upon the interval over which the turnover measurement was made, while in the heart NE turnover doubled in response to the same cold stimulus In animals exposed to cold continuously for 10 d before study, NE turnover measurements in IBAT and in the heart were elevated comparably to those obtained during acute exposure Alterations in feeding were also associated with changes in NE turnover in IBAT Fasting for 2 d decreased NE turnover in IBAT (-35% from 292+/-42 ng NE/h to 189+/-59) and in heart (-52%) In animals fed a "cafeteria" diet, a model of voluntary overfeeding in the rat, NE turnover was increased in both IBAT (+108% from 248+/-45 ng NE/h to 517+/-68) and heart (+66%) Because ganglionic blockade exerted a greater effect on NE turnover in IBAT in cafeteria-fed rats than in controls, the increase in NE turnover in IBAT with this overfeeding regimen reflects enhanced central sympathetic outflow Thus NE turnover techniques can be satisfactorily applied to the assessment of sympathetic nervous system activity in IBAT The experiments reported here demonstrate changes in sympathetic activity in IBAT that parallel known adaptive changes in heat production in the rat These studies, therefore, support the concept that the increased thermogenesis of chronic cold exposure and of cafeteria feeding occur by similar mechanisms and imply an important role for the sympathetic nervous system, mediated in part through BAT, in the regulation of energy balance in the rat

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Effect of Diet and Cold Exposure on Norepinephrine Turnover in Brown Adipose Tissue of the Rat

It is well established that electrical stimulation of the ventromedial hypothalamus (VMH) causes a reduction in food intake, whereas electrolytic or chemical lesions in this area result in hyperphagia and obesity in the rat. This has led to the suggestion that either the ventromedial nucleus itself, or nerve fibres passing close by, are important in the control of food intake. However, obesity due to VMH lesions occurs in weanling rats in the absence of hyperphagia and can develop in adult rats pair-fed with controls, indicating that destruction of this area also causes an increased metabolic efficiency (that is, a reduced energy expenditure). In normal rats, hyperphagia induced by feeding a highly palatable cafeteria diet is often accompanied by a large increase in heat production (diet-induced thermogenesis) which tends to prevent excessive weight gain and obesity1. This diet-induced thermogenesis is due to sympathetic activation of brown adipose tissue (BAT) and we have now investigated the possibility that the VMH is involved in the activation of this process. We found that electrical stimulation of this area produced increased BAT thermogenesis, which suggests that the VMH exerts a dual influence in the regulation of energy balance—an inhibitory effect on energy intake and a stimulatory effect on thermogenesis and energy output.

Activation of brown adipose tissue thermogenesis by the ventromedial hypothalamus

To investigate the effect of SR141716, a selective CB1 receptor antagonist, on energy expenditure and on glucose uptake in isolated soleus muscle of Lepob/Lepob mice. Female Lepob/Lepob mice (8–10 weeks old) were treated with SR141716 (10 mg/kg, i.p. once daily) or vehicle for 7 days. Oxygen consumption, daily food and water intake, body weight and glucose uptake in isolated soleus muscle. SR141716 (10 mg/kg, i.p. once daily) resulted in a significant reduction of daily food intake (P<0.01) and body weight (P<0.05) 5 days after daily treatment. Body weight continued to be lower for the rest of the treatment period (P<0.05). There was no significant difference in body weight between the pair-fed and vehicle-treated animals. A 7-day treatment with SR141716 (10 mg/kg, i.p. once daily) caused 37% increase in basal oxygen consumption compared to that of vehicle-treated (90 min mean; P<0.01), and a significant 68% increase in glucose uptake in isolated soleus muscle preparations. It is concluded that SR141716 has a direct effect on energy expenditure suggesting that the antiobesity effect of SR141716 is due to activation of thermogenesis in addition to the initial hypophagia. The increase in soleus muscle glucose uptake with SR141716 treatment may contribute to the improved glycaemia seen in the previous studies.

Michael J. Stock

Papers

A role for brown adipose tissue in diet-induced thermogenesis

A role for brown adipose tissue in diet-induced thermogenesis

Effect of Diet and Cold Exposure on Norepinephrine Turnover in Brown Adipose Tissue of the Rat

Activation of brown adipose tissue thermogenesis by the ventromedial hypothalamus

Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice.