Question

After completing your degree you are hired by a world-leading drug company that has developed a new drug called EX-factor that enhances basal (resting) levels of fatty acid oxidation in skeletal muscle. EX-factor has undergone extensive safety testing and there are no reported side effects. It has been shown to “boost” the amount of fatty acids that are completely oxidized in skeletal muscle by ~30% at rest and is therefore being touted as “exercise in a pill”. The company has hired you, an expert in type 2 diabetes pathophysiology and exercise science, to advise on the outcome measures they should use in the first placebo-controlled randomized controlled trial testing EX-factor in patients with type 2 diabetes.

Answer the following questions related to EX-Factor and this proposed trial.

a) If Ex-Factor works by activating an enzyme, what enzyme do you think EX-Factor might be activating to increase basal fatty acid oxidation? Choose only one enzyme in your answer.

b)If Ex-Factor works by increasing an intracellular metabolite or molecule, what metabolite/molecule do you think it might be increasing to increase basal fatty acid oxidation in mitochondria? Choose only one metabolite/molecule.

c) If Ex-Factor works by increasing a hormone in the blood, what hormone do you think might be increasing to enhance basal fatty acid oxidation? Choose only one hormone or category of hormone.

d) If Ex-Factor works by reducing a hormone in the blood, what hormone do you think might be reducing to enhance basal fatty acid oxidation? Choose only one hormone or category of hormone.

Answer 1

a) If Ex- factor works by activating an enzyme, then it should be acyl - CoA synthetase which catalyze the activation of Fatty acid before its oxidation.

FATTY ACID + CoA + ATP ---------> acyl-CoA +AMP+PPi

b) If Ex- Factor works by increasing a metabolite then it should be Acyl CoA. The Acyl CoA is the intermediatary product for the active fatty acid oxidation. It is transported across mitochondria for Beta oxidation

c) If Ex factor works by increasing a hormone in blood, it should be Epinephrine. Fatty Acid oxidation is controlled by hydrolysis rate of triacylglycerols in adipose tissue by hormone sensitive triacylglycerol lipase. Epinephrine and norepinephrine act to increase adipose tissue cAMP concentrations. cAMP allosterically activates cAMP dependent protein kinase increasing the phosphorylation levels of the enzymes . Phosphorylation activates the hormone sensitive lipase and stimulating Lipolysis in adipose tissue and activating beta oxidation pathway in tissues such as liver and muscle.

d) If Ex- factor works by reducing a hormone, it should be Insulin. Insulin has opposite effect of glucagon and epinephrine. It stimulates the formation of glycogen and triacyl glycerols. This protein hormone which is secreted in response to high glucose concentration, decreases cAMP level. This situation can lead to the dephosphorylation and thus the inactivation of hormone sensitive lipase thereby reducing the amount of fatty acids available for oxidation.