Tackling obesity with a new therapeutic target

Governments across the globe are looking to develop the most effective solutions for tackling the serious challenge that obesity now presents.

Looking at the UK, it is estimated that the direct costs to the National Health Service of treating obesity is £6 billion ($8.5 billion), with 2015 figures showing prevalence to be as high as 27%. Furthermore, in the US, the rate for adults is even higher and stood at a staggering 36.5%.

As a consequence, obesity has been labelled ‘‘a national emergency’’ by Britian’s health secretary and, in 2001, an ‘‘epidemic crisis’’ by US surgeon general David Satcher. Moreover, this crisis reaches way beyond North America and Western Europe, with rates rising rapidly in China and India to match high rates across Middle Eastern countries.

Traditionally, obesity has been characterised as an energetic imbalance through which caloric intake outweighs energy expenditure - resulting in a BMI of above 30. This is primarily due to a rise in sugar and dietary fat consumption, together with increasingly sedentary lifestyles.

Obesity is a risk factor for a host of chronic conditions including cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), as well as osteoarthritis, and certain forms of cancer. In addition to its metabolic nature, recent research findings imply that obesity is actually a form of chronic low grade inflammation. Once visceral fat depots become excessively large, the surrounding areas tend to become characterised by secretion of pro-inflammatory cytokines, for example, TNF-α, and proliferation and infiltration of inflammatory immune cell types – such as M1 macrophages, Th1 and cytotoxic lymphocytes - over anti-inflammatory types like M2 macrophages, eosinophils and Treg tolerance lymphocytes.

Utilisation of fiscal policy tools and regulation to affect spending and consumption decisions, has, to date, been the primary means of targeting obesity by governments. Good examples include increased food labelling, sugar taxes and investment in obesity education, particularly amongst those socio-economic groups that tend to be most at risk, namely, low income families.

The problem, though, is that these methods have limited efficacy, in part due to the proliferation of cheap foods that are high in sugar and fat. The tendency thus far in pharmaceutical methods that target obesity has been to use sympathomimetic β-adrenergic agonists as a means of promoting lipolysis, fatty acid oxidation and insulin activity. T

However, these have been severely limited due to non-specific, off-target effects, particularly on cardiovascular pathways, as well as loss of efficacy with chronic use. In addition, another method of targeting obesity centres on bariatric surgery by either decreasing the stomach size or rerouting the small intestine. This has shown some promise in terms of efficacy, but the problem is that significant limitations still remain including resultant nutrional difficiencies, healthcare system resource constraints and difficulties in performing invasive surgery on obese patients.

As a consequence, utilising brown adipose tissue (BAT) as a therapeutic tool for obesity has, become increasingly attractive to the healthcare sector. Whilst white adipose tissue (WAT) is able to store lipids and assume a pro-inflammatory phenotype in the obese conditions, BAT provides the capability to oxidise lipids and burn fat via a uniquely expressed mitochondrial membrane protein called UCP1. This protein bypasses the ATP synthase mechanism of proton transport across the mitochondrial membrane - which produces chemical energy in the form of ATP - to enable protons to ‘leak’ across the membrane through UCP1, generating heat energy in the process.

UCP1 activation in mammals occurs primarily upon cold activation. Cold stimulation of the sympathetic nervous system causes the release of adrenergic agonist noradrenaline, which activates β-3 adrenergic receptors on the BAT surface. Through a downstream signalling cascade, which includes cAMP, PGC-1α and peroxisome proliferator-activated receptor gamma (PPAR-γ), UCP1 is eventually activated and heat generated to counteract cold sensation.

This is an important means for heat generation in small mammals undergoing hibernation as well as infant humans unable to generate heat through shivering response. There is, however, a significant problem. Masses of BAT decrease dramatically in adult humans, eventually becoming restricted to small deposits, mainly in the neck region. Indeed, the existence of BAT in humans was only confirmed in 2009 using FDG-PET scans. As well as what is known as classical or canonical BAT (which has a distinctive developmental lineage from WAT), a third type of adipose tissue exists, which is 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 antipose tissue.

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

To date, four different approaches have emerged for using BAT to target metabolic disorders like obesity. One is cold activation, though this has a practical limitation as it requires extended periods of cold exposure with limited clothing coverage. Secondly, there is a pharmaceutical approach which aims to activate classical BAT or beige reserves by targeting β-3 adrenergic receptors in a similar way to sympathomimetics. A third method is to differentiate stem cells or WAT into BAT or beige adipocytes ex vivo - transplating the tissue as a cell therapy. The fourth option is to consume foods able to either recruit and activate BAT or trans-differentiation of WAT into beige, brown-like adipocytes. Future pharmaceutical approaches may also aim to use BAT, in this way, to target type 2 diabetes and obesity.

In summary, the limited availability of human BAT in vitro for screening purposes has hampered finding new compounds that are able to activate BAT without the disadvantages associated with sympathomimetics. Solutions are however at hand. Innovation in the form of bead-based combinatorial screening has been utilised to develop protocols able to differentiate stem cells into human BAT in vitro. Industry partnerships have been formed for the development of screening platforms with the goal of identifying new, plant extract derived compounds for the recruitment and activation of brown antipose tissue in humans.

About the author:

Shahzad Ali is a senior scientist at Plasticell.