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Can Exercise Help You Lose Weight?

Physical exercise consumes energy — in fact, it activates fat metabolism and makes white fat turn into brown fat, which burns energy. So why can’t we prove that exercise helps you lose weight? Well, it’s complicated…

Caroline Apovian, MD

Fat tissue metabolically plays different roles during different stress situations on the body. During exercise, fat tissue also has to maintain body temperature and overall systemic energy balance. This is true for both acute and chronic exercise states.

Recent studies suggest that increased fat metabolism and the browning of white fat and also a reduction in brown fat thermogenesis may both be triggered by exercise — at different time intervals.

This explains the conflicting studies showing both at play after exercise. A resolution to these conflicting results may be realized with studies looking at “real time” stimulation: in vivo studies.

What Have Studies Shown So Far?

Brown adipose tissue (BAT) biomarkers are proteins with special thermogenic properties. Uncoupling protein 1 (UCP1) is located on the inner membrane of mitochondria and causes protein leaks by reducing adipose tissue protein (ATP) synthesis. Activation of UCP1 increases thermogenesis in BAT and starts the browning process in white adipose tissue (WAT).

Exercise stimulates the secretion of batokines secreted by BAT. Some of these batokines are fibroblast growth factor 21 (FGF21), bone morphogenic protein 8B (BMP8b), interleukin-6, vascular endothelial growth factor A (VEGF-A), insulin-like growth factor 1, neuroregulatory protein 4, the lipokine 12,13-diHOME, and microRNAs.

Acute exercise has been shown to increase 12,13-diHOME levels in humans and mice, which increases skeletal muscle fatty acid uptake and oxidation. Exercise has been also found to increase hepatic and plasma FGF21 and VEGF-A expression in WAT.

However, exercise-induced VEGF-A in BAT has not been reported. It’s hard to prove that these elevations are indeed coming from BAT during exercise. These batokines are not BAT biomarkers, but they nonetheless affect nutrient metabolism. They serve as mediators or crosstalk molecules between BAT and other organs.

The problem in humans is that there is not much BAT — and therefore finding what exercise does to activate BAT is difficult.

What Else Do We Know About What Exercise Does Systemically?

Exercise causes adipose tissue browning through a molecular network starting with stimulation of sympathetic nerves, which releases norepinephrine to bind to B adrenergic receptors; this starts adipose tissue thermogenesis and, therefore, browning.

Exercise also promotes the release of irisin in muscle as well as hepatic release of FGF21. Irisin can brown adipocytes directly and also promote brain-derived neurotrophic factor from the brain via muscle brain crosstalk, which also increases thermogenesis and browning.

Circulating metabolites such as creatine, acetate, and free fatty acids produced by exercise also enhance adipose tissue thermogenesis and browning directly and indirectly. All of these molecular pathways lead in the same direction. So what is the conflicting evidence?

It turns out that BAT thermogenesis in endurance athletes is lower than that in sedentary persons. The acute vs chronic effect of exercise on thermogenesis and browning is different. In addition, there seem to be differences in animals and humans regarding the antioxidant effect of UCP1.

If we consider human studies, it may be that there is an explanation regarding acute and chronic exercise. An increase in thermogenesis results in a higher body core temperature. When the core temperature rises to dangerous levels to the body, the BAT thermogenesis needs to cool down to maintain other physiologic cellular activities. If we look at the body as a whole and not just the muscle and adipose tissue during exercise, we may be able to understand the conflicting studies of what happens to thermogenesis during exercise.

A hypothesis offered recently by Zhu et al proposes that an increase in BAT thermogenesis stimulated by exercise is temporary, and that it’s competing for the same glucose and free fatty acid oxidation that the muscle needs to do the exercise.

Again looking at the body as a whole, it could be that there is a trigger for the downregulation of energy going to BAT so that energy can go towards skeletal muscle. Perhaps some studies are capturing the increase in heat production in BAT and others are capturing a reduction in heat production in BAT due to a different snapshot in the time course of exercise.

How Do We Measure This Accurately?

Adipocyte thermogenesis is most often equated with browning. Browning means that there are more mitochondria in adipocytes, whereas thermogenesis is the process of oxidative phosphorylation uncoupling via UCP1 — a UCP1-mediated proton leak. The energy stored in protein gradients in the mitochondria is coupled with ATP synthesis.

But the energy can be lost in the form of heat if it fails to synthesize the high energy bonds of ATP and UCP1 operates as the heat producer. UCP1 removes the coupling between electron transfer and phosphorylation in the respiratory chain so that oxidative phosphorylation enters an idle state. This is called a proton leak.

If this hypothesis is true, it provides an answer to what’s going on during exercise. We can measure the redox state of each organ system during exercise and derive an energy potential across the cytoplasm that reflects the energy state of the cell. In other words, is the cell in the process of storing or utilizing energy? Is the excess energy being converted to heat or stored?

Currently we are not measuring these states in vivo in real time. What we can say is that somehow, chronic exercise seems to maintain a certain body composition that is a deterrent to weight gain. We just don’t understand yet how this works.

Exercise activities in vivo don’t occur in isolation but as part of a complex metabolic pathway that somehow senses each cell in the body — and this may occur through redox states measured by the potential of each cell — or each organ as a whole.

Exercise-induced fat browning doesn’t explain why exercise can help maintain a weight loss, at least not by itself in isolation. The body is a complex system that somehow works to maintain a certain body weight and adjusts the metabolism of each cell towards this goal.

Exercise seems to help maintain weight loss through muscle communicating with the brain and with adipose tissue and perhaps other organ systems. Exactly how this is achieved is the focus of ongoing research.

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