Increasing a protein concentrated in brown fat appears to lower blood sugar, promote insulin sensitivity, and protect against fatty liver disease by remodeling white fat to a healthier state, a new study led by UT Southwestern scientists suggests.
The finding, published online in Nature Communications, could eventually lead to new solutions for patients with diabetes and related conditions.
“By taking advantage of this natural system, we may be able to help make fat depots more metabolically healthy and potentially prevent or treat obesity-associated diabetes,” says study leader Perry E. Bickel, M.D., associate professor of internal medicine at UTSW.
Tens of millions of Americans have Type 2 diabetes, a disease characterized by elevated blood sugar and resistance to insulin, the hormone that allows cells to use blood sugar for energy.
This disease has been linked to obesity, with excess white adipose tissue (WAT) – fat tissue that holds the majority of the body’s stored energy – associated with elevated blood sugar and insulin resistance in susceptible people.
Humans and other mammals also have a second type of fat, known as brown adipose tissue (BAT), which is able to burn fat as a way to increase body heat in cold temperatures. BAT has been investigated as a potential target for weight loss, says Bickel, but may also have a role in improving blood sugar independent of weight loss.
In the study, Bickel and his colleagues, including co-leader Violeta I. Gallardo-Montejano, M.D., an instructor at UTSW, found that brown fat could play an important protective role against diabetes. The researchers made this discovery while studying perilipin 5 (PLIN5), a protein that coats lipid droplets inside cells, particularly in BAT.
When the team genetically engineered mice that made extra PLIN5 in BAT, the animals maintained significantly lower blood sugar concentrations and higher insulin sensitivity during glucose tolerance tests, compared with mice with normal PLIN5 levels. They also had less fatty livers, a condition associated with Type 2 diabetes.
Searching for the mechanism behind these positive changes, the scientists found that the BAT’s mitochondria in the genetically engineered mice had adapted to burn even more fat, similar to what’s seen in animals placed in cold temperatures. However, the adaptation wasn’t enough to explain the blood sugar-lowering effect.
Looking closer, the researchers found that the white adipocytes of animals that had extra PLIN5 in their brown adipocytes were smaller and had reductions in some markers of inflammation – changes that are associated with improved sensitivity to insulin and metabolism of sugar.
Bickel notes that BAT appears to communicate with WAT in some unknown way, potentially sending a molecular factor through the bloodstream when PLIN5 levels increase inside brown adipocytes.
“The next question we want to address,” says Bickel, “is what that factor is and whether we can harness it for therapeutic benefit.”
rown adipose tissue (BAT) was considered, for several years, to be present only in newborns and small mammals to generate heat through non-shivering thermogenesis as protection against hypothermia. However, the abundant amount of active BAT in children declines rapidly after puberty.
The exact amount (volume) of active BAT in adult humans remains highly variable, but the prevalence of brown adipose tissue in adults was estimated at 6.97% based on recently published results from a systematic review and meta-analysis . The first clinical observations of BAT came from oncological patients in whom imaging scans, using positron emission tomography combined with computed tomography (PET/CT) or magnetic resonance PET/MR, revealed cervical adipose tissue characterized by high metabolic activity . In 2009, functional brown fat in adult humans was confirmed after dedicated cold exposure research [3,4,5].
The increased worldwide prevalence of obesity has prompted the scientific world to search for new possibilities to deal with weight gain . Obesity is a major health risk factor and strongly associated with the development of insulin resistance, which is a key player in the pathogenesis of metabolic complications, type 2 diabetes, and cardiovascular diseases . An increased obesity rate is associated with a decrease in life expectancy and also represents a large economic burden .
BAT is a type of tissue designed for maintaining body temperature higher than ambient temperatures through heat production, primarily via non-shivering thermogenesis. This process is mediated by the expression of uncoupling protein 1 (UCP1) within the inner membrane of the abundant mitochondria .
Despite high mitochondria content and high cellular respiration rates, brown adipocytes have a remarkably low capacity for adenosine triphosphate (ATP) synthesis . Brown adipocytes (in contrast to most human cells), through UCP1 expression and low ATP synthase activity, diminish the proton gradient by uncoupling cellular respiration and decrease mitochondrial ATP synthesis to stimulate heat production.
Due to its unique UPC1, brown adipose tissue has been acknowledged as a promising approach to increase energy expenditure . In other words, BAT burns fat and increases the metabolic rate, promoting a negative energy balance . Moreover, BAT alleviates metabolic complications like dyslipidemia, impaired insulin secretion, and insulin resistance in type 2 diabetes .
The protective role of BAT, in terms of its metabolic consequences, prompted the molecular exploration of brown adipocyte differentiation. The most relevant molecular factors involved in brown and white adipose tissue formation are peroxisome proliferator-activated receptors (PPARs) . PPARγ has a crucial role in tissue development and functions by inducing UCP1 expression during adipogenesis .
Moreover, PPARγ agonists can be used to induce the browning of white adipose tissue , while PPARα activation promotes beige adipogenesis via Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which is a key regulator of mitochondrial biogenesis, adaptive thermogenesis, and oxidative metabolism.
In the molecular pathways involved in white adipose tissue (WAT) browning, the key factor is PR domain-containing protein 16 (PRDM16), which controls the switch between skeletal myoblasts and brown adipocytes and stimulates adipogenesis by directly binding to PPARγ .
Recently, it was shown that brown and beige adipocytes release growth and differentiation factor 15 (GDF15) in response to thermogenic activity. GDF15 may mediate the downregulation of local inflammatory pathways . Moreover, in adipose tissue biology, certain microRNAs play the important role of regulating BAT and WAT functions and differentiation. Such microRNAs regulate white, brown, and beige adipogenesis by targeting key transcription factors (e.g., PRDM16, PPARγ, CCAAT-enhancer binding protein C/EBPB, and PGC1α) .
The aim of this review is to explore the role of BAT in whole-body energy expenditure and lipid and glucose homeostasis and to discuss new possible activators of brown adipose tissue in humans to treat obesity and metabolic disorders.
More information: Violeta I. Gallardo-Montejano et al, Perilipin 5 links mitochondrial uncoupled respiration in brown fat to healthy white fat remodeling and systemic glucose tolerance, Nature Communications (2021). DOI: 10.1038/s41467-021-23601-2