Nutrition and Gene Expression Lecture, Part 2: Feb 26, 2015 Activation of PDK-4 and coordinated expression of fat oxidation in muscle: effects of fasting, followed by glucose intake

This research builds on a body of knowledge that indicates that maintenance of low insulin promotes a “lipid catabolic” pathway, especially during exercise High cortisol/high glucagon/high epinephrine, along with low insulin, promotes release of fatty acids from adipose, and these fatty acids are transported to muscle on albumin Muscle that is “primed” can then readily oxidize fatty acids through beta-oxidation in the muscle mitochondria, as shown on the next slide The RQ (respiratory quotient) is an index of either: CARBOHYDRATE OXIDATION (RQ=1) FATTY ACID OXIDATION (RQ=0.7) In the following paper, the fasted subjects during exercise approached an RQ of 0.75, indicated >70% fat oxidation. That changed after glucose ingestion!

Glucose ingestion during exercise blunts exercise-induced gene expression of skeletal muscle fat oxidative genes Anthony E. Civitarese, Matthijs K. C. Hesselink, Aaron P. Russell, Eric Ravussin and Patrick Schrauwen

Experimental design: -male volunteers, college-age, in good health, not endurance-trained -overnight fast -moderate exercise (to 50% power output); this could likely be attained by most college students on a frequent basis -each subject was examined in 2 separate protocols. 1) Each protocol: Cycle for 2 hours (a long bike ride), and then rest for 3hours 2) Part A: Control experiment: no glucose was provided at all 3) Part B: Ingest glucose, cycle for 120 minutes, with additional glucose ingestion during and following the exercise -during the protocol, frequent blood samples and muscle biopsies were obtained for measurements.

In the following slides: The diamond shapes ( ♦ ) are data collected under control conditions (no glucose). The squares ( ■ ) are data collected during glucose supplementation. Each volunteer did the control trial and the glucose trial.

GLUCOSE INGESTION ( ■ ) HAD SEVERAL EFFECTS: -raised blood sugar (upper left) -blocked release of free-fatty acids to bloodstream (FFA) (upper right) -led to a rise in the RQ, which is a shift toward carbohydrate oxidation

This important graph (both groups are superimposed, leads to a major conclusion: 50 kJ/min = 12 kcal/min. If 75% of the energy comes from fat (low carb group), that’s 1 gram/min, or about 100 grams total. What is the conclusion: this exercise, if done fasting, can use of 4 ounces of stored fat per session. If done daily, >1 pound/week.

MOST OF THESE mRNA ARE FOR GENES LINKED TO INSULIN METABOLISM. ON THE LOWER RIGHT IS DATA FOR PDK-4. THE INCREASE IS BLOCKED BY GLUCOSE INGESTION! THIS DATA COMPARES THE FASTED AND GLUCOSE PHASE, FOR EACH VOLUNTEER.

The mRNA for UCP3 and CD36, which are involved in fatty acid oxidation, is stimulated by fasting exercise. Ingestion of carbs brings down expression of CPT-1

This paper established some important conclusions about exercise, both fasting and following carbohydrate ingestion. -fatty acid release, and its oxidation (estimated from the RQ) are favored by exercise in the fasting state -the expression of key genes for fatty acid oxidation is increased by exercise in the fasting state, as estimated by mRNA levels in muscle biopies HOWEVER, this paper does not really address MECHANISMS for the change in the activity of these genes. To develop that concept, the next paper (Furuyama et al), examines the FOXO family of transcription factors and their role in regulation of PDK-4.