IMPC: Is Lrg1 an autocrine/paracrine regulator of thermogenesis in brown and beige adipose tissue? Implications for cardiometabolic disease.

Background: Our bodies store excess energy as fat inside special cells, called white fat cells (that form white adipose tissue). But not all fat cells are the same; brown fat cells (brown adipose tissue) break down stored fat to generate heat during exposure to cold, while beige fat cells can switch between the two, either storing or burning fat.
It is thought that brown and beige fat cells have protective properties against obesity and type 2 diabetes, due to their fat burning activity. However, during aging and obesity the amount of brown and beige fat in our bodies decreases, while the amount of white fat increases. This may contribute to an increased risk of developing metabolic diseases such a type 2 diabetes. We do not yet fully understand why the amount of brown and beige fat decreases during obesity. Our experiments suggest that fat cells release a protein signal, known as Lrg1, which may enter the blood and decrease the fat burning ability of brown and beige fat cells. Lrg1 is increased in the blood of people with type 2 diabetes, and those who are obese. The concentration of Lrg1 in blood also increases with age. We don't yet know for certain whether Lrg1 decreases the fat burning ability of beige and brown fat in the body, or whether this contributes to accelerated development of type 2 diabetes.

Research aims: This research in Dr Roberts' laboratory will determine whether "turning off" the gene for Lrg1 increases the amount of beige and brown fat cells, and their ability to burn fat. The research will also investigate whether switching off the Lrg1 gene protects against obesity and type 2 diabetes.

Potential benefit to society and people with diabetes: Type 2 diabetes is a worldwide healthcare challenge; with an estimated 422 million people thought to have type 2 diabetes globally. In the UK the NHS spends £14 billion a year to treat diabetes. Understanding how obesity increases the risk of developing this disease, may lead to new treatments to target the twin global epidemics of obesity and type 2 diabetes. By studying the role Lrg1 plays in regulating the fat burning capacity of beige and brown fat cells, this research hopes to identify whether Lrg1 is a potential new therapy target to protect against the loss of beige and brown fat and the onset of obesity and type 2 diabetes.

Significance: An estimated 422 million people worldwide suffer from Type 2 Diabetes (T2D), making the discovery of novel therapeutics imperative.
Context: Brown and beige adipose tissue are characterized by high levels of fatty acid oxidation, mitochondrial biogenesis and thermogenesis. Thermogenesis in beige and brown adipocytes alters systemic energy balance with anti-obesity and anti-diabetic effects. Brown and beige fat mass and thermogenic capacity decrease with age and obesity.
Leucine-rich-alpha2-glycoprotein 1 (Lrg1) is a liver and adipose-associated secreted protein. Lrg1 plasma concentration is correlated with age, body mass index, and adiposity, suggesting a role in obesity. Our data indicate that Lrg1 inhibits thermogenic gene expression in beige and brown adipose tissue.
Aim: To determine whether Lrg1 contributes to obesity related brown and beige adipose loss, and subsequent pathophysiology, using the Lrg1tm1(KOMP)Vlcg mouse.
Objectives: 1) Establish an Lrg1tm1(KOMP)Vlcg mouse colony at the University of Leeds. 2) Investigate the effect of Lrg1 knockout on the brown and subcutaneous adipose tissue metabolic phenotype. 3) Assess the metabolic effect of Lrg1 knockout in a dietary-induced mouse model of T2D.
Methodology: The effect of Lrg1 knockout on the phenotype of brown and subcutaneous adipose tissue will be investigated using molecular biology and metabolic approaches. The effect of Lrg1 knockout on metabolic parameters (weight, body composition, energy expenditure and glucose/insulin homeostasis) will be assessed in a dietary-induced T2D mouse model. Analysis of systemic metabolic phenotypes including indirect calorimetry, activity and food intake, body composition, and glucose/insulin homeostasis will be conducted using metabolic cages, MRI imaging and glucose and insulin tolerance tests.
Applications: This research may identify whether Lrg1 contributes to the pathophysiology of obesity; and highlight Lrg1 as a therapeutic target for T2D.