Perspective: Does brown fat protect against diseases of aging?

Abstract

The most commonly studied laboratory rodents possess a specialized form of fat called brown adipose tissue (BAT) that generates heat to help maintain body temperature in cold environments. In humans, BAT is abundant during embryonic and early postnatal development, but is absent or present in relatively small amounts in adults where it is located in paracervical and supraclavicular regions. BAT cells can 'burn' fatty acid energy substrates to generate heat because they possess large numbers of mitochondria in which oxidative phosphorylation is uncoupled from ATP production as a result of a transmembrane proton leak mediated by uncoupling protein 1 (UCP1). Studies of rodents in which BAT levels are either increased or decreased have revealed a role for BAT in protection against diet-induced obesity. Data suggest that individuals with low levels of BAT are prone to obesity, insulin resistance and cardiovascular disease, whereas those with higher levels of BAT maintain lower body weights and exhibit superior health as they age. BAT levels decrease during aging, and dietary energy restriction increases BAT activity and protects multiple organ systems including the nervous system against age-related dysfunction and degeneration. Future studies in which the effects of specific manipulations of BAT levels and thermogenic activity on disease processes in animal models (diabetes, cardiovascular disease, cancers, neurodegenerative diseases) are determined will establish if and how BAT affects the development and progression of age-related diseases. Data from animal studies suggest that BAT and mitochondrial uncoupling can be targeted for interventions to prevent and treat obesity and age-related diseases. Examples include: diet and lifestyle changes; specific regimens of mild intermittent stress; drugs that stimulate BAT formation and activity; induction of brown adipose cell progenitors in muscle and other tissues; and transplantation of brown adipose cells.

Figure 1

BAT: its location, cellular composition and thermogenic regulation. A. In humans brown adipose tissue (BAT) is located in interscapular and supraclavicular regions of the thorax, and is innervated by sympathetic nervous system (SNS) neurons that originate in the hypothalamus (HT) (Bamshad et al., 1999). Cold temperatures and excessive food intake activate the SNS resulting in increased BAT thermogenic activity. B. Cellular features of BAT. The principal cell of BAT is the brown adipose (BA) cell which contains large numbers of mitochondria that utilize energy substrates and O2 and generate heat which is transferred to circulating blood. BAT also contains brown adipose progenitors (BAP) which are capable of dividing and differentiation into BA cells. BAT is innervated by axons from sympathetic neurons that employ the neurotransmitter norepinephrine (NE). C. Thermogenic signal transduction in brown adipocytes. NE released from SNS presynaptic terminals activates adrenergic receptors (R) on the surface of BA cells, resulting in the activation of the GTP-binding protein gs which, in turn, activates adenylate cyclase (AC) to generate cyclic adenosine monophosphate (cAMP). Cyclic AMP then activates cAMP-dependent protein kinase (PKA) which then phosphorylates and thereby activates lipases that hydrolyze triacylglycerols to generate free fatty acids (FFA). The FFA are then transferred into mitochondria where they undergo β-oxidation to generate acetyl Co A (AcCoA) which enters the citric acid cycle (CAC). As a result of b-oxidation and the CAC the energy substrates FADH (flavanine adenine dinucleotide) and NADH (nicotinamide adenine dinucleotide) are generated. BA cells express high amounts of uncoupling protein 1 (UCP1) which, when activated by the pathway just described, mediates a proton leak that uncouples the electron transport chain resulting in heat production.

Figure 1

BAT: its location, cellular composition and thermogenic regulation. A. In humans brown adipose tissue (BAT) is located in interscapular and supraclavicular regions of the thorax, and is innervated by sympathetic nervous system (SNS) neurons that originate in the hypothalamus (HT) (Bamshad et al., 1999). Cold temperatures and excessive food intake activate the SNS resulting in increased BAT thermogenic activity. B. Cellular features of BAT. The principal cell of BAT is the brown adipose (BA) cell which contains large numbers of mitochondria that utilize energy substrates and O2 and generate heat which is transferred to circulating blood. BAT also contains brown adipose progenitors (BAP) which are capable of dividing and differentiation into BA cells. BAT is innervated by axons from sympathetic neurons that employ the neurotransmitter norepinephrine (NE). C. Thermogenic signal transduction in brown adipocytes. NE released from SNS presynaptic terminals activates adrenergic receptors (R) on the surface of BA cells, resulting in the activation of the GTP-binding protein gs which, in turn, activates adenylate cyclase (AC) to generate cyclic adenosine monophosphate (cAMP). Cyclic AMP then activates cAMP-dependent protein kinase (PKA) which then phosphorylates and thereby activates lipases that hydrolyze triacylglycerols to generate free fatty acids (FFA). The FFA are then transferred into mitochondria where they undergo β-oxidation to generate acetyl Co A (AcCoA) which enters the citric acid cycle (CAC). As a result of b-oxidation and the CAC the energy substrates FADH (flavanine adenine dinucleotide) and NADH (nicotinamide adenine dinucleotide) are generated. BA cells express high amounts of uncoupling protein 1 (UCP1) which, when activated by the pathway just described, mediates a proton leak that uncouples the electron transport chain resulting in heat production.

Figure 1

BAT: its location, cellular composition and thermogenic regulation. A. In humans brown adipose tissue (BAT) is located in interscapular and supraclavicular regions of the thorax, and is innervated by sympathetic nervous system (SNS) neurons that originate in the hypothalamus (HT) (Bamshad et al., 1999). Cold temperatures and excessive food intake activate the SNS resulting in increased BAT thermogenic activity. B. Cellular features of BAT. The principal cell of BAT is the brown adipose (BA) cell which contains large numbers of mitochondria that utilize energy substrates and O2 and generate heat which is transferred to circulating blood. BAT also contains brown adipose progenitors (BAP) which are capable of dividing and differentiation into BA cells. BAT is innervated by axons from sympathetic neurons that employ the neurotransmitter norepinephrine (NE). C. Thermogenic signal transduction in brown adipocytes. NE released from SNS presynaptic terminals activates adrenergic receptors (R) on the surface of BA cells, resulting in the activation of the GTP-binding protein gs which, in turn, activates adenylate cyclase (AC) to generate cyclic adenosine monophosphate (cAMP). Cyclic AMP then activates cAMP-dependent protein kinase (PKA) which then phosphorylates and thereby activates lipases that hydrolyze triacylglycerols to generate free fatty acids (FFA). The FFA are then transferred into mitochondria where they undergo β-oxidation to generate acetyl Co A (AcCoA) which enters the citric acid cycle (CAC). As a result of b-oxidation and the CAC the energy substrates FADH (flavanine adenine dinucleotide) and NADH (nicotinamide adenine dinucleotide) are generated. BA cells express high amounts of uncoupling protein 1 (UCP1) which, when activated by the pathway just described, mediates a proton leak that uncouples the electron transport chain resulting in heat production.

Figure 2

Possible mechanisms by which BAT and mitochondrial uncoupling can protect against obesity and age-related diseases. See text for discussion.