The mitochondria in a
eukaryotic cell utilize fuels to produce
adenosine triphosphate (ATP). This process involves storing energy as a
proton gradient, also known as the
proton motive force (PMF) generated by moving protons from the
mitochondrial matrix (N or negative side) across the
mitochondrial inner membrane to the
mitochondrial intermembrane space (P or positive side) using the energy released by the
electron transport chain. This proton gradient energy is used to synthesize ATP when the protons flow across the membrane (down their concentration gradient - from a region of high proton concentration to a region of lower proton concentration) through the
ATP synthase complex; this is known as
chemiosmosis. In
endotherms, body heat is maintained by signaling the mitochondria to allow protons to move back into the mitochondrial matrix (down their concentration gradient - from a region of high proton concentration to a region of lower proton concentration) without producing ATP (proton leak). This can occur since an alternative return route for the protons exists through an
uncoupling protein in the inner membrane. This protein, known as uncoupling protein 1 (
thermogenin) - which is unique to brown adipose tissue, facilitates the return of the protons after they have been actively pumped out of the mitochondrial matrix by the
electron transport chain. This alternative route for protons
uncouples oxidative phosphorylation and the energy in the PMF is instead released as heat. To some degree, all cells of endotherms give off heat, especially when body temperature is below a regulatory threshold. However, brown adipose tissue is highly specialized for this non-shivering
thermogenesis. First, each cell has a higher number of mitochondria compared to more typical cells. Second, these mitochondria have a higher-than-normal concentration of thermogenin in the inner membrane.
Infants In
neonates (newborn infants), brown fat makes up about 5% of the body mass and is located on the back, along the upper half of the spine and toward the shoulders. It is of great importance to avoid
hypothermia, as lethal cold is a major death risk for premature neonates. Numerous factors make infants more susceptible to cold than adults: • A higher ratio of body surface area (proportional to heat loss) to body volume (proportional to heat production) • A higher proportional surface area of the head • A low amount of musculature and the inability to
shiver • A lack of thermal insulation, e.g., subcutaneous fat and fine body hair (especially in prematurely born children) • An inability to move away from cold areas, air currents or heat-draining materials • An inability to use additional ways of keeping warm (e.g., drying their skin, putting on clothing, moving into warmer areas, or performing physical exercise) • A nervous system that is not fully developed and does not respond quickly and/or properly to cold (e.g., by contracting blood vessels in and just below the skin:
vasoconstriction). Heat production in brown fat provides an infant with an alternative means of heat regulation.
Adults of a
hibernoma, a benign
tumour thought to arise from
brown fat (
haematoxylin and eosin stain) It was believed that after infants grow up, most of the mitochondria (which are responsible for the brown color) in brown adipose tissue disappear, and the tissue becomes similar in function and appearance to white fat. In rare cases, brown fat continues to grow, rather than
involuting; this leads to a
tumour known as a
hibernoma. It is now known that brown fat is related not to white fat, but to skeletal muscle. Studies using
positron emission tomography scanning of adult humans have shown that brown adipose tissue is still present in most adults in the upper chest and neck (especially paravertebrally). The remaining deposits become more visible (increasing tracer uptake, meaning more metabolically active) with cold exposure, and less visible if an adrenergic
beta blocker is given before the scan. These discoveries could lead to new methods of
weight loss, since brown fat takes calories from normal fat and burns it. Scientists have been able to stimulate brown fat growth in mice. One study of APOE knock out mice showed cold exposure could promote
atherosclerotic plaque growth and instability. The study mice were subjected to sustained low temperatures of 4 °C for 8 weeks which may have caused a stress condition, due to rapid forced change rather than a safe acclimatisation, that can be used to understand the effect on adult humans of modest reductions of ambient temperature of just 5 to 10 °C. Furthermore, several newer studies have documented the substantial benefits of cold exposure in multiple species including humans, for example researchers concluded that "activation of brown adipose tissue is a powerful therapeutic avenue to ameliorate hyperlipidaemia and protect from atherosclerosis" and that brown fat activation reduces plasma triglyceride and cholesterol levels and attenuates diet-induced atherosclerosis development. Long-term studies of adult humans are needed to establish a balance of benefit and risk, in combination with historical research of living conditions of recent human generations prior to the current increase of poor health related to excessive accumulation of white fat. Pharmacological approaches using β3-adrenoceptor agonists have been shown to enhance glucose metabolic activity of brown adipose tissue in rodents. Additionally research has shown: • Brown adipose tissue activation improves glucose homeostasis and insulin sensitivity in humans suggesting that anyone with impaired insulin function might benefit from BAT activation; however, there is broader application given research showing even mildly elevated blood glucose in healthy non-diabetic humans is associated with damage over time of many organs such as eyes, tendons, endothelial/cardiovascular system and brain, and results in higher levels of damaging
advanced glycation end products. • Brown adipose tissue activation may play an important role in bone health and
bone density. • Brown adipose tissue activation through cold exposure increases
adiponectin levels, just two hours of cold exposure resulted in a 70% increase in circulating adiponectin in adult men.
Centenarians (both men and women) and their offspring have been found to have genetics that boost adiponectin, and they have higher circulating adiponectin, suggesting a link between longevity and adiponectin production. In addition, high concentrations of plasma adiponectin in centenarians was associated with favorable metabolic indicators, and with lower levels of C-reactive protein and E-selectin. • Cold exposure increases circulating
irisin. Irisin improves insulin sensitivity, increases bone quality and quantity, is involved in the building of lean muscle mass, and helps reduce obesity by converting white fat to brown fat, providing many of the same benefits of exercise. Healthy centenarians are characterized by increased serum irisin levels, whereas levels of this hormone were found to be significantly lower in young patients with myocardial infarction. These findings may prompt further research into the role played by irisin not only in vascular disorders but also in life span modulation. •
Fibroblast growth factor 21 (FGF-21) production has been documented as a pathway to longevity. BAT activation through cold exposure up-regulates circulating fibroblast growth factor 21 (FGF21) in humans by 37%. which may partially explain its longevity promoting benefits. • Under basal environmental temperatures,
HDAC3 primes expression of
UCP1 and the brown fat thermogenic program to ensure acute cold survival through the deacetylation and activation of
PGC-1alpha. • Cold exposure increases
SIRT1 phosphorylation/activity in both skeletal muscle and BAT, increasing thermogenesis and insulin sensitivity through deacetylation of
PGC-1alpha and other protein targets. Elevated SIRT1 levels in people are associated with increased human longevity. SIRT1 (and the other
sirtuins) have many metabolic effects, but an important one for improving health and longevity is the fact that SIRT1 increases insulin sensitivity and glucose control in skeletal muscles, triggers the browning of white fat and increases BAT activity. ==Other animals==