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Increased Energy Efficiency Might Drive Weight Regain

This is a possible reason why some weight loss interventions stop working.

Depressed obeseDepressed obese

Scientists have discovered that formerly obese mice that became leaner have greatly improved energy efficiency, which might be preventing their complete return to normal weight [1].

ย Why is it so hard to lose the last few pounds?

People attempting to lose weight often feel like their own bodies are fighting them, as shedding additional pounds becomes an uphill battle. These people often become frustrated when they maintain or even regain weight when maintaining previously effective routines.

There is a documented mechanism that protects against weight changes by altering the bodyโ€™s energy efficiency [2]. One study found that the decline in energy expenditure following weight loss (something that makes additional weight loss harder) stems from increased energy efficiency, specifically in skeletal muscle [3]. However, the exact workings of this mechanism had remained unclear.

Massive increase in OXPHOS efficiency

In this new study, the researchers hypothesized that weight loss improves the efficiency of mitochondrial respiration in skeletal muscle. To investigate this, they took wild-type mice and fed them an obesogenic diet for 10 weeks. Then, the mice in this study group were divided into two subgroups: half of the animals continued to receive their high-fat, high-carbohydrate chow, while the rest were put on a standard diet to induce weight loss.

Over the next 10-12 weeks, the average weight of the mice who had been put back on the standard diet (the weight loss group) declined and then stabilized above the level of the control group that was fed non-obesogenic chow from the start (the lean group). In other words, the mice that gained and then lost weight ended up weighing less on average than the obese mice but more than the mice that never experienced weight gain in the first place.

The researchers found that VO2, the total volume of consumed oxygen and a commonly used metric of energy expenditure, was much higher in the obese mice than in the two other groups, which would be consistent with their higher weight. However, in the lean and the weight loss groups, VO2 levels were largely identical despite the weight difference. Since the weight loss group was not less physically active than the lean group, the difference must have been in the metabolic rate.

Changes in VO2 were not associated with adipose tissue. However, in skeletal muscle, weight loss induced a massive 50% increase in the efficiency of oxidative phosphorylation (OXPHOS), the fundamental process of energy production in cells. OXPHOS occurs in mitochondria and produces large amounts of ATP, the molecule that supplies energy for cells. Basically, the mice that had lost weight now needed much less oxygen to produce the same amount of ATP. OXPHOS efficiency in the other two groups was largely identical.

Lipids, not proteins

Interestingly, this impressive improvement in OXPHOS efficiency was not accompanied by any significant changes to the skeletal muscle mitochondrial proteome. Not a single mitochondrial protein showed statistically different levels in the obese and the weight loss groups. If the ATP-producing machinery remained the same, what did change?

The whole OXPHOS โ€œfactoryโ€ based on five protein complexes is embedded in the inner mitochondrial membrane, which is built from a familiar lipid bilayer. Unlike with the proteome, there were some differences in the muscle mitochondrial lipidome. The researchers noticed that in the weight loss group, TLCL, a type of lipid, was significantly elevated compared to two other groups. Previous research has linked TLCL to OXPHOS efficiency [4]. Knocking down TAZ, an enzyme crucial for TLCL production, increased energy expenditure (i.e., lowered energy efficiency), protecting the mice from diet-induced obesity.


This study shows that weight loss induces a striking 50% increase in energy efficiency compared to situations of both continuous normal weight and obesity. This means that after having lost weight, someone might need to do 50% more work to burn the same number of calories. While the researchers did identify a potential target for intervention, the road to the clinic might be very long. Meanwhile, just being aware of this phenomenon is valuable information that might prevent frustration for people trying to lose instead of regain weight.

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[1] Patrick J Ferrara, Marisa J Lang, Jordan M Johnson, Shinya Watanabe, Kelsey L McLaughlin, J Alan Maschek, Anthony R P Verkerke, Piyarat Siripoksup, Amandine Chaix, James E Cox, Kelsey H Fisher-Wellman, Katsuhiko Funai (2023). Weight loss increases skeletal muscle mitochondrial energy efficiency in obese mice, Life Metabolism

[2] Ravussin, Y., Edwin, E., Gallop, M., Xu, L., Bartolomรฉ, A., Kraakman, M. J., … & Ferrante Jr, A. W. (2018). Evidence for a non-leptin system that defends against weight gain in overfeeding. Cell metabolism, 28(2), 289-299.Chicago

[3] Goldsmith, R., Joanisse, D. R., Gallagher, D., Pavlovich, K., Shamoon, E., Leibel, R. L., & Rosenbaum, M. (2010). Effects of experimental weight perturbation on skeletal muscle work efficiency, fuel utilization, and biochemistry in human subjects. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 298(1), R79-R88.

[4] Prola, A., Blondelle, J., Vandestienne, A., Piquereau, J., Denis, R. G., Guyot, S., … & Pilot-Storck, F. (2021). Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle. Science Advances, 7(1), eabd6322.

CategoryDiet, News
About the author
Arkadi Mazin

Arkadi Mazin

Arkadi is a seasoned journalist and op-ed author with a passion for learning and exploration. His interests span from politics to science and philosophy. Having studied economics and international relations, he is particularly interested in the social aspects of longevity and life extension. He strongly believes that life extension is an achievable and noble goal that has yet to take its rightful place on the very top of our civilizationโ€™s agenda โ€“ a situation he is eager to change.
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