Chewing the fat

Having already reached epidemic levels, the search for pharmaceutical approaches to tackle obesity has been tough – could clues lay in brown fat? Shahzad Ali takes up the case…

Indeed, the alarm bells are now ringing loud and clear across the international healthcare community, especially as forecasts predict an increase in obesity levels across all studied countries. In response, Governments across the world are looking to develop the most effective solutions for tackling the serious challenge that obesity presents.

With huge impact on the average cost of healthcare, obesity is a problem that needs to be tackled fast. Taking the UK as an example, it is estimated that the prevalence of obesity reached a massive 26% in 2016, leaving the National Health Service with a bill of £6 billion worth of direct costs from treating obesity-related illness. In the USA, the rates for adults were even higher, standing at a staggering 36.5%. By 2017, statistics in OECD countries indicated that one in two adults and nearly one in six children were overweight or obese.

Moreover, this crisis reaches way beyond North America and Western Europe, with rates rising rapidly in China and India, and the Middle East being the region with the second highest obesity rates globally. As early as 2001, the US Surgeon General, David Satcher, referred to the situation as an “epidemic crisis”, while the British Secretary of State for Health has labelled obesity “a national emergency” – statements which reflect the terrifying reality of obesity.

Utilising brown adipose tissue (BAT) – better known as brown fat – as a therapeutic tool for obesity has become increasingly attractive to the healthcare sector

The immune link

Obesity is traditionally defined as a state of excessive adipogenicity caused by an energetic imbalance whereby caloric intake outweighs energy expenditure ­­­– resulting in a body mass index (BMI) above 30. The primary reasons for climbing obesity rates are an increase in sugar and fat consumption due to the increasingly processed nature of readily available foods, as well as a trend towards a more sedentary lifestyle across the world.

While adipocytes are heavily involved in metabolic regulation, recent research highlights their role in blood pressure control, haemostasis, thyroid activity, reproductive function and importantly, immune response. In obesity, once visceral fat depots become excessively large, the surrounding areas become characterised by secretion of pro-inflammatory cytokines, for example TNF-?, IL-1, IL-6, IL-8, and IFN?. These cytokines stimulate the proliferation and infiltration of inflammatory immune cells such as cytotoxic T-lymphocytes, T-helpers and M1 macrophages.

Stimulation of the inflammatory immune response in adipocytes eventually leads to chronic, low-grade, inflammation which is associated with the development of chronic conditions such as type II diabetes, cardiovascular disease, certain forms of cancer and osteoarthritis. The reduction of obesity is therefore a pressing problem in tackling chronic illness.

A new tool

Governments are currently utilising fiscal policy to influence spending and consumption decisions as a primary means to tackle obesity. Good examples include increased food labelling, sugar taxes, and investment in obesity education campaigns amongst those socio-economic groups that tend to be more at risk (namely, low-income families). However, these methods have limited efficacy due to the increasing availability of cheap foods that are high in sugar and fats.

In addition, another method of targeting obesity centres on bariatric surgery – either decreasing the stomach size or rerouting the small intestine. This has shown some promise in terms of efficacy, however significant limitations remain, including resultant nutritional deficiencies, healthcare system resource constraints and difficulties in performing invasive surgeries on obese patients. The search for pharmaceutical methods to target obesity has so far focused on the use sympathomimetic ?-adrenergic agonists as a means of promoting lipolysis, fatty acid oxidation and insulin activity. The problem, however, is that usage is severely limited due to non-specific, off-target effects, particularly on cardiovascular pathways, as well as loss of efficacy with chronic use.

As a consequence, utilising brown adipose tissue (BAT) – better known as brown fat – as a therapeutic tool for obesity has become increasingly attractive to the healthcare sector.

Golden brown

Unlike the more common white adipose tissue (WAT) that stores lipids and assumes a pro-inflammatory phenotype in obesity, brown-adipose tissue (BAT) provides the capability to oxidize lipids and burn fat via a uniquely expressed mitochondrial membrane protein called UCP1 - producing heat.

The UCP1 proteins are activated in mammals primarily upon cold stimulation of the sympathetic nervous system. This stimulation results in the release of adrenergic agonist noradrenaline - activating ?-3 adrenergic receptors on the BAT surface. Through a downstream signalling cascade, which includes PGC-1?, peroxisome proliferator-activated receptor gamma (PPAR-?) and cAMP, UCP1 is activated allowing protons to move across the mitochondrial inner membrane without stimulating ATP synthase. This decoupling of proton movement and ATP production means that the electron gradient is not used to create traditional chemical energy, in the form of ATP, but produces heat instead, to counteract cold sensation.

This process is an important means for heat generation in both small mammals undergoing hibernation and human infants unable to generate heat through shivering response. Unfortunately, there is a significant problem with using brown adipose tissue to tackle obesity. In adult humans, BAT volumes decrease dramatically, eventually becoming restricted to small deposits mainly in the neck. Indeed, the existence of small amounts of BAT in adult humans was only confirmed in 2009 using FDG-PET scans. Up until that discovery point, the prevailing view amongst most scientists was that brown fat was only to be found in babies

In addition to what is often referred to as classical or canonical BAT (which has a distinctive developmental lineage from WAT), there also exists a third type of adipose tissue, called beige or BRITE cells. These are brown-like adipocytes ­– characterised by high mitochondrial content and thermogenic potential – within WAT depots that follow a similar developmental lineage to white adipose tissue.

Though brown adipose tissue is rare in adults, higher ratios of BAT volume compared to WAT have been associated with lower rates of obesity and type 2 diabetes due to its increased insulin sensitivity and energy expenditure capability. As a result, BAT has now emerged as a highly attractive therapeutic target for obesity treatment.

Utilising BAT

Scientists have devised four approaches that utilise BAT as a means of targeting metabolic disorders, especially obesity. One of them is cold activation. However, this technique has a practical limitation since it requires extended periods of cold exposure with limited clothing coverage. Secondly, a pharmaceutical approach is applied which aims to activate classical brown adipose tissue or beige reserves by targeting ?-3 adrenergic receptors in a way that is similar to sympathomimetics – a method which has been shown to improve glucose tolerance and insulin sensitivity. The third, and highly compelling method is to differentiate stem cells or WAT into BAT or beige adipocytes ex vivo – with the tissue then transplanted as a cell therapy. The fourth option is the consumption of foods able to either recruit and activate brown adipose tissue, or cause trans-differentiation of WAT into BRITE (brown-like adipocytes). Future pharmaceutical approaches may also aim to use BAT, in this way, to target both obesity and type 2 diabetes.

Finding new compounds able to activate brown adipose tissue without the disadvantages associated with sympathomimetics has been hindered by the limited availability of human BAT in vitro for the purposes of screening. There are however effective solutions in development.

Innovative methods exist in the form of bead-based combinatorial screening, which have been used to develop protocols that are capable of differentiating stem cells into human BAT in vitro. R&D initiatives are already in place which are directed at achieving the industry’s goal of identifying new compounds based on plant-derived natural extracts ­– for the recruitment and activation of brown adipose tissue in humans. Industrial partnerships have been established to develop the screening platforms required for this crucial task.

Author

Shahzad Ali is Senior Scientist at Plasticell