Introduction: Recent observation of brown adipose tissue (BAT) being functional in adult humans provides a rationale for its stimulation to increase energy expenditure through ‘adaptive thermogenesis’ for an anti-obesity strategy. Many endocrine dysfunctions are associated with changes in metabolic rate that over time may result in changes in body weight. It is likely that human BAT plays a role in such processes.
Review: In this brief review article, we explore the endocrine determinants of BAT activity, and discuss how these insights may provide a basis for future developments of novel therapeutic strategies for obesity management.
A review of electronic and print data comprising original and review articles retrieved from PubMed search up to December 2013 was conducted (Search terms: brown adipose tissue, brown fat, obesity, hormone). In addition, relevant references from the articles were screened for papers containing original data.
Conclusion: There is promising data to suggest that targeting endocrine hormones for BAT modulation can yield a cellular bioenergetics answer for successful prevention and management of human obesity. Further understanding of the physiological link between various endocrine hormones and BAT is necessary for the development of new therapeutic options.
Alex’s Notes: There are two main types of adipose tissue, white (WAT) and brown (BAT), that evolved to save us from famine and freezing, respectively. Cold-induced activation of BAT has been found in adult humans, and it has been shown conclusively via radio-labeled fatty acid tracers that BAT does indeed contribute to energy expenditure. Unlike WAT, BAT contains many mitochondria that have faulty membranes because of the expression of uncoupling protein 1 (UCP1). This allows them to take up fat and glucose to burn for energy, except that all the energy is lost as heat that contributes to non-shivering thermogenesis.
So how does our body handle BAT?
Like most things, hormones are the main regulator of BAT activity, and there are a surprising number of them. We have known for well over a century that thyroid hormones (TH) increase metabolism and heat production (thermogenesis), but TH also enhances mitochondrial respiration through stimulation of mitochondrial biogenesis and of the expression of genes implicated in the regulation of their ability to produce energy. These effects are evident in the cold-intolerant and metabolically impaired individuals suffering from hypothyroidism, and in the sweating energy factories of those with hyperthyroidism. These effects are clinical manifestations of altered BAT activity, and in fact, thyroid receptor (TR) β mediates thyronine (T3) induced UCP1 gene expression, while the TRα regulates facultative thermogenesis in BAT.
The catecholamines adrenaline and noradrenaline also stimulate BAT activity through the beta-3 adrenergic receptor, which activates UCP1 expression via the cyclic adenosine monophosphate (cAMP) and protein kinase-A (PKA) pathways. Again, this is evident in persons with phaeochromocytoma (excessive catecholamine production from an adrenal tumor) who demonstrate increased BAT activity during PET/CT scans.
Growth hormone has been shown to increase inter-scapular brown fat mass at very high doses (3.5 mg/kg/day) in mice, although lower doses (1 mg/kg/day) showed no such effect despite an increase in UCP1 mRNA by 2.8 fold. Additionally, Insulin Growth Factor-1 (IGF-1) receptors are highly expressed in the plasma membrane of rat BAT with a probable role for BAT differentiation and activation. Insulin also stimulates BAT to uptake glucose and fat for usage in a manner similar to its effects on WAT. In fact, BAT is demonstrated to be one of the most insulin-sensitive tissues in rodents, and chronic insulin deficiency reduces the thermogenic capacity of BAT. How these results translate into humans is debatable, but it may explain why many ketogenic and low-carbohydrate dieters suffer from cold-intolerance (which could also be a side-effect of reduced sympathetic output and reduced thyroid hormones).
Not all hormones are BAT-friendly, however. The glucocorticoids such as cortisol have been shown to have an inhibitory effect on BAT activity in rodents, likely from an inhibition in the expression and function of the beta-1 and beta-3 adrenergic receptors within BAT. Mineralocorticoids like aldosterone have similar effects through inhibition of UCP1 expression, increased WAT inflammation, and decreased thermogenesis. Finally, prolactin is a crucial hormone in adipogenesis and carbohydrate metabolism, and prolactin receptor knockout mice subjected to a high fat diet for 16 weeks exhibited resistance to weight-gain, a reduction in WAT, and 2–3 fold increased expression of BAT-specific markers compared to controls.
Finally, a discussion on hormone regulation isn’t complete without mention of the sex hormones. Ovariectomy in female rodents reduced BAT mitochondrial functionality through reduction in the oxidative capacity and anti-oxidant defenses, but estradiol supplementation partially reversed these effects indicating its partial influence on BAT. Additionally, young females show greater BAT activity than their post-menopausal counterparts. Testosterone on the other hand actually reduces the thermogenic and lipolytic ability of BAT, while progesterone has the exact opposite effect. DHEA, when administered to obese and lean rats, caused reduced food intake and enhanced energy expenditure resulting in weight-loss through increased expression of Pgc-1α, Ucp1 and β3-Ar.
So how can we (ab)use these effects for weight-loss?
Well, GC-1 is a selective TRβ agonist that induces UCP1 gene expression in rats and primates, resulting in increased energy expenditure and reduced fat mass without the negative cardiovascular effects of T3. Stimulants for increased catecholamine output would also help, provided you don’t mind being jittery and irritable. Avoiding chronic stress will help with cortisol and maintaining “optimal” (whatever that means) sex hormone status may be of interest, at least to women who have gone through menopause.
And then of course you could just run and lift heavy things, as exercise stimulates the release of irisin from skeletal muscle (also another reason to have a lot of muscle; i.e. metabolic currency). Irisin is a great little hormone that shows a powerful ability to “brown” WAT, resulting in increased energy expenditure and improved glucose tolerance.
But in all fairness, I just wouldn’t worry about it. Much of the research is conducted in rodents, and although BAT has been detected in adult humans, its relevance and application to our lives is largely unknown. It will be interesting to see what becomes of BAT in the future. Knowing us (that is, humans), we will likely find a way to abuse its power in a manner more pleasant than taking DNP (2,4-dinitrophenol; look it up).