Dissecting thermogenesis by brown adipose tissue and skeletal muscle in lean and obese subjects

The number of people who are either overweight or obese continues to increase, and being obese increases your risk of developing many other diseases such as type 2 diabetes, high blood pressure, heart disease, certain cancers and reduces life expectancy. Obesity is also associated with a higher risk of dying from covid-19. As such, new treatments for obesity are urgently required to improve health. Weight loss can be achieved either by reducing how much energy we eat or by increasing the amount of energy we burn. When people gain weight the amount of fat in your body increases, this is also called 'white fat' and this type of fat is there mainly to store excess energy. However, there is another type of fat in your body called brown fat, this is a very special type of fat in that its main role is to burn energy to keep us warm when we're in a cold environment. Interestingly, people who are obese have less brown fat than people of normal weight, importantly though obese people who do have brown fat are less likely to develop diabetes and heart disease than obese people without brown fat. The amount of brown fat we have in our body can also be increased, as such there is much interest in working out how to activate brown fat as a new treatment to help reduce the chances of developing diabetes or heart disease. However, our understanding of how brown fat generates heat is not well understood, in part this is because it is difficult to measure its activity in humans and relies on special types of scans. It is also unclear whether the brown fat in obese individuals doesn't function properly compared to the brown fat in lean people.

In this research we will measure how brown fat works in lean and obese people when they are placed in the warm and the cold. We will place special tubes in the brown fat, white fat and muscle tissue of lean and obese adults to measure how much sugar, fat and other substances these tissues use when generating heat. This will allow us to build a more complete picture of how brown fat uses these substances to produce heat. We have previously shown that brown fat in humans produces a lot of a substance called lactate, we will also work out the importance of lactate to brown fat function and how brown fat uses this lactate to generate heat. Finally, we know that brown fat can communicate with other important tissues in the body to improve health, we will investigate how brown fat does this by measuring which substances brown fat produces in lean and obese adults. This research will reveal how brown fat produces its beneficial effects on health and identify how obesity changes brown fat function. This may well identify new targets which will allow us to develop new treatments to make brown fat work better. This may in time lead to better therapies to help people lose weight, treat diabetes and prevent heart disease.

The identification of brown adipose tissue (BAT) in adult humans ~15 years ago led to substantial interest in activating BAT to increase energy expenditure as a novel tool to treat obesity and associated metabolic disease. However, our understanding of the pathways regulating BAT activation and even how BAT utilises metabolic substrates during thermogenesis remains limited. Even the fate of glucose uptake by BAT is unclear, although we previously demonstrated high lactate production by human BAT. A major problem is the reliance on PET imaging that cannot detect uptake and release of multiple substrates in real time. While glucose uptake by BAT is reduced in obese subjects (the target patient group), whether this causes defective BAT thermogenesis or compensatory activation in other pathways is unknown. In addition, BAT positive status improves metabolic outcomes, potentially through communication with other metabolic organs but how this occurs is unclear. In this research project we will develop arterio-venous sampling of BAT and skeletal muscle as a novel technique and use this in combination with microdialysis to to quantify substrate utilisation by BAT, skeletal muscle and white adipose tissue (WAT) in lean and obese volunteers during warm and cold exposure in real time. We will also infuse 13C-glucose to determine the fate of glucose in vivo and the fate of multiple substrates in vitro using our primary human brown and white adipocyte and myoblast cell models. We will determine the role of the lactate receptor in BAT using our in vitro models and also in vivo using mice with global disruption of this receptor. Finally, we will perform proteomics/peptidomics analyses on blood and dialysate to identify the in vivo BAT secretome for the first time to identify potential candidates with therapeutic potential. This research will identify key thermogenic pathways and any dysregulation in obesity, this may identify targets for subsequent therapeutic manipulation.