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Heeding the call for action against diabetes, obesity
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During the past 3 decades, we have been fighting an uphill battle against the pandemics of obesity and diabetes. Rates of both have increased dramatically during the span of only one generation.
With these pandemics come a myriad of associated metabolic and neoplastic disorders that affect every organ of the body. Once only possible in those wealthy enough to afford whatever they wanted to eat, obesity is now a disease of the poor because the agricultural revolution has led to the paradoxical situation in which the least expensive foods are the simple carbohydrates that are low in nutrition and insufficiently trigger satiety.
Aaron M. Cypess
Even more concerning is that these diseases are afflicting the young, in particular. No longer does it make sense to refer to juvenile diabetes, unless one is discussing type 2, which is now found in higher rates than autoimmune diabetes. Worse, the burden of carrying excess weight at a younger age appears to be even more extreme than in adults, setting us up for a public health crisis by the middle of this century.
Meantime, the threat of these diseases has led to a remarkable series of discoveries that have given the endocrine community much greater knowledge about metabolism and the way our organs communicate with each other. White adipose tissue (WAT) was thought to be a passive storage depot until 20 years ago, when it was determined that it is instead an endocrine organ regularly releasing hormones such as leptin, which reports the body’s energy stores to the brain and helps regulate appetite and energy expenditure. White adipokines such as tumor necrosis factor-alpha reflect how the tissue responds to stress and the ensuing maladaptive physiological changes. Newly described pathways in the central nervous system regulating satiety have finally lent themselves to pharmacological intervention, including regulators of the 5HT2c and cannabinoid receptors. The stress of a pandemic has triggered a response, and it is finally promising.
Focus on BAT
One of the areas of great interest is the activation of human brown adipose tissue (BAT). An organ designed to consume calories and generate heat, human BAT is undergoing a second renaissance. More than 3 decades ago, interest in the tissue grew because it was determined that, in rodents, maximally stimulated BAT could consume nearly 20% of its daily energy expenditure. Unfortunately, drugs designed to activate its relatively tissue-specific beta-3 adrenergic receptor (AR) were not effective, and it was thought that this failure was due to an absence of BAT in adult humans. It took the introduction of 18F-FDG PET/CT in the early 2000s for BAT to return to center stage. With a new method capable of noninvasively measuring whole-body activity in a prospective manner, we learned that human BAT was present in a large proportion of adult humans, in regions different from the rodent, and this activity could be regulated. The immediate future of human BAT research will focus on three areas by which the organ could provide therapeutic benefit.
Energy expenditure
The most obvious therapeutic use for human BAT thermogenesis is on energy balance. Certainly, in rodents, BAT energy expenditure is central to its metabolism, and there are several lines of evidence showing that increasing its mass through cold activation, beta-3 AR agonists or transplantation leads to protection against weight gain and improved glucose tolerance. However, there are still critical unanswered questions. Humans are 2,000-times larger than mice but have only 200-times more BAT. There just may not be enough to have a clinical effect.
Another concern is that, at this time, it is unknown how much BAT contributes to the increased energy expenditure seen during the standard mild cold exposure studies. The body may expend an additional several hundred kcal/day, but it is unclear if human BAT is contributing most, some or nearly none of that increased energy expenditure. An interesting twist to this conundrum is that evidence from rodent models shows that the much larger WAT depot is capable of browning, and this process can even take over when there is a loss of the principal interscapular BAT depot. Whether the source of calorie-consuming fat comes from WAT or BAT remains to be seen.
Glucose metabolism
To support its thermogenesis, human BAT consumes both glucose and triglycerides. In fact, cold exposure induces a higher rate of glucose uptake per gram of BAT than any other organ in the body. In cold-acclimatized mice, this effect is enough to have a clinically meaningful effect of the uptake of ingested glucose. Will activation of human BAT have a role in treating hyperglycemia? More studies are clearly needed.
Hormonal regulation
There clearly are questions as to whether human BAT can overcome its relatively small size to influence energy balance or blood glucose levels. One area where mass is irrelevant is in the realm of hormones. We now recognize that WAT is a complex endocrine organ, and it is logical to believe that BAT must be as well. Two decades ago, it was shown that rodent BAT activity affects pancreatic beta-cell function, and the recent finding in BAT of betatrophin, a hormone that profoundly expands beta-cell mass, may be one reason why. With so little currently known about BAT adipokines and the potential for effects on metabolism so great, the next few years may bring the rapid discovery and translation of new hormones and drugs toward the treatment of obesity and metabolic disease.
In response to the increasing global rates of obesity and diabetes, the endocrine community is rising to the challenge. We are learning more about cellular physiology and the signaling networks that interconnect every tissue. Human BAT, which was only recently identified as a functional organ, may be able to affect metabolism in several ways. The next few years promise to be ones of discovery and, hopefully, success in finding treatments for the billions of people worldwide with metabolic disease.