The effect of inorganic nitrate on systemic energy homeostasis in a setting of perturbed energy balance: implications for diabetes and obesity.

Summary

The World Health Organization estimates 500 million people worldwide are obese and over 340 million suffer from type 2 diabetes (T2D). The quality of life of these individuals and the burden to healthcare make the discovery of novel therapeutics or interventions imperative.

Inorganic nitrate is found in many dietary foodstuffs, with a high concentration observed in green leafy vegetables. Nitrate was considered a non-bioactive metabolite of NO and a potentially toxic dietary constituent1. However, nitrate has since been shown to reduce blood pressure and the oxygen demand of exercise; indicating that this anion may be beneficial for metabolic health2,3. Recent complementary studies demonstrated that nitrate treatment led to anti-obesity and anti-diabetic effects in endothelial NOS-deficient mice, a strain prone to a metabolic syndrome–like phenotype4.

Moreover, studies conducted by the Dr Roberts and co-workers have identified that nitrate has distinct metabolic effects on both skeletal muscle and adipose tissue; nitrate increased mitochondrial biogenesis and fatty acid oxidation in skeletal muscle (SKM), activated the thermogenic programme in brown adipose tissue (BAT), and induced the “browning response”, a switch from a white adipose like-phenotype to a brown adipose-like phenotype in subcutaneous white adipose tissue (WAT)5-7.

The metabolic effects of nitrate in adipose and skeletal muscle indicate increased energy expenditure within these independent tissues. Increasing energy metabolism may be a viable therapeutic strategy for treating obesity and T2D, however the systemic effect of nitrate on whole body energy metabolism in a setting of perturbed energy balance, as seen in obesity is, as yet, unknown.

Aim:

This PhD project will examine the physiological effects of inorganic nitrate on whole-body systemic energy balance and metabolism in dietary induced models of obesity and type 2 diabetes.

Project:

A multidisciplinary approach, employing metabolic and in vivo imaging techniques, will be utilized to phenotype the effects of inorganic nitrate on systemic energy homeostasis in dietary-induced mouse models of obesity and type 2 diabetes. Employing the state-of-the-art preclinical imaging facility (which includes high-field MRI, optical imaging, CT and PET/CT) within the Leeds Institute of Cardiovascular and Metabolic Medicine, in vivo longitudinal measures of body composition and BAT, WAT and SKM metabolic activity in the mouse models will be made (MRI, PET/CT).

Metabolic phenotyping will include determination of whole body metabolic phenotypes using an advanced Comprehensive Lab Animal Monitoring System (CLAMS), which enables the accurate measurement of weight, food and water intake, activity, indirect calorimetry and respiratory quotient and exchange ratios using specialized metabolic cages. Glucose and insulin tolerance tests will be employed to monitor glucose homeostasis.

PhD training opportunities:

The project will suit a student with a background in physiology, biochemistry or related discipline with a strong interest in diabetes and metabolism. The multidisciplinary project provides training in cutting-edge physiological / metabolic phenotyping and imaging techniques.

References:

Moncada, S. The L-arginine: nitric oxide pathway, cellular transduction and immunological roles. Adv Second Messenger Phosphoprotein Res 28, 97-9 (1993).

Larsen, F.J., Ekblom, B., Sahlin, K., Lundberg, J.O. & Weitzberg, E. Effects of dietary nitrate on blood pressure in healthy volunteers. N Engl J Med 355, 2792-3 (2006).

Larsen, F.J., Weitzberg, E., Lundberg, J.O. & Ekblom, B. Effects of dietary nitrate on oxygen cost during exercise. Acta Physiol (Oxf) 191, 59-66 (2007).

Carlstrom, M. et al. Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice. Proc Natl Acad Sci U S A 107, 17716-20 (2010).

Roberts, L.D. et al. Inorganic nitrate promotes the browning of white adipose tissue through the nitrate-nitrite-nitric oxide pathway. Diabetes 64, 471-84 (2015).

Roberts, L.D. et al. Inorganic Nitrate Mimics Exercise-Stimulated Muscular Fiber-Type Switching and Myokine and gamma-Aminobutyric Acid Release. Diabetes 66, 674-688 (2017).

Ashmore, T. et al. Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism. BMC Biol 13, 110 (2015).

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.