When people talk about "high-quality weight loss," they are describing fat-selective weight loss—dropping excess fat while keeping muscle intact.

 

The Problem with Traditional Weight Loss

Most standard weight-loss interventions work by cutting calories, whether through a low-calorie diet or appetite-suppressing medications like GLP-1 receptor agonists. However, these methods don't just reduce fat; they also cause the body to shed lean mass, which is largely muscle.

While individual results vary, lean muscle accounts for roughly 30% of total weight lost during conventional calorie restriction. [1–3]

 

Why Losing Muscle Is Dangerous

Muscle is far more than just a tool for movement—it is an important player in metabolic health:

     - Metabolic Rate: Muscle is a primary driver of resting metabolic rate (how many calories your body burns at rest)

     - Blood Sugar Control: Muscle plays a critical role in healthy glucose metabolism

     - Functional Strength: Muscle provides the mobility and strength needed for daily life, which becomes especially vital as we age

 

The Science Behind "Yo-Yo" Weight Regain

When you lose weight by reducing food intake, your body actively fights back to defend an internal target level of fat—a mechanism often referred to as the body's "adipostat" or “weight setpoint”. As a result, your resting energy expenditure (metabolic rate) slows down significantly. This drop happens for two main reasons:

     1. Loss of Muscle Mass: With less muscle tissue, the body naturally burns fewer calories at rest

     2. Adaptive Thermogenesis: The body purposefully turns down its internal furnace to conserve energy and push you back toward your previous weight. [6–8]

This double-hit to your metabolism drives the well-known "yo-yo" effect — the rapid weight regain that often follows a low-calorie diet or the discontinuation of a GLP-1 medication. [1–4]

To make matters worse, during this regain phase, the body builds back fat several times faster than it rebuilds lean muscle. This phenomenon — known as "preferential catch-up fat" — can leave a patient with a higher body fat percentage than when they started treatment. [3–7] Because obesity is fundamentally a disease of excess fat mass rather than overall weight, this outcome can leave the patient metabolically worse off than they were before they started to lose weight.

 

A High-Quality Alternative: Resetting the Setpoint

An ideal obesity treatment would target fat loss almost exclusively.

In preclinical animal studies, approaches that induce weight loss by increasing energy expenditure, specifically by expanding active brown fat mass, cause weight loss that comes from body fat, but with no detectable loss of lean muscle.

Unlike calorie restriction, increasing energy expenditure has the potential to lower the body's adipostat. While genetic and environmental factors can dysregulate this setpoint and cause weight gain, evidence shows that it can also be reset to a lower, healthier level. [9–11]

 

The Energesis Approach

Energesis is developing therapies designed to raise resting energy expenditure and lower the weight the body naturally defends. By shifting the focus from simply eating less to burning energy more effectively, the goal is to deliver true fat-selective, high-quality weight loss that is also far more durable than weight loss driven by calorie restriction alone.

 

Preclinical Disclaimer: Energesis' programs, including EGS-2632, are currently in preclinical development. They have been evaluated only in laboratory and animal models and have not yet been tested in humans. They are not approved by any regulatory authority, and preclinical results may not predict human safety or efficacy.

 

Sources

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2. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med. 1995 Mar 9;332(10):621-8. doi: 10.1056/NEJM199503093321001. Erratum in: N Engl J Med 1995 Aug 10;333(6):399. PMID: 7632212.

3. Dulloo AG. Physiology of weight regain: Lessons from the classic Minnesota Starvation Experiment on human body composition regulation. Obes Rev. 2021 Mar;22 Suppl 2:e13189. doi: 10.1111/obr.13189.

4. Dulloo AG, Jacquet J, Montani JP. Pathways from weight fluctuations to metabolic diseases: focus on maladaptive thermogenesis during catch-up fat. Int J Obes (Lond). 2002;26(Suppl 2):S46-S57.

5. Dulloo AG, Jacquet J, Seydoux J, Montani JP. The thrifty ‘catch-up fat’ phenotype: its impact on insulin sensitivity during growth trajectories to obesity and metabolic syndrome. Int J Obes (Lond). 2006;30 (Suppl 4):S23-S35. https://doi.org/10.1038/sj.ijo.0803516

6.  Dulloo AG, Jacquet J, Girardier L. Poststarvation hyperphagia and body fat overshooting in humans: a role for feedback signals from lean and fat tissues. Am J Clin Nutr. 1997 Mar;65(3):717-23. doi: 10.1093/ajcn/65.3.717.

7. Dulloo AG, Jacquet J. Adaptive reduction in basal metabolic rate in response to food deprivation in humans: a role for feedback signals from fat stores. Am J Clin Nutr. 1998 Sep;68(3):599-606. doi: 10.1093/ajcn/68.3.599. PMID: 9734736.

8. Thivel D, Doucet É, Lazzer S, Montaurier C, Pereira B, Bosy-Westphal A, Muller MJ, Boirie Y, Isacco L. Adaptive thermogenesis in response to weight loss and weight regain: first evidence in adolescents with severe obesity. Br J Nutr. 2026 Jan 28;135(2):149-155. doi: 10.1017/S0007114525105837.

9.  Boss O, and Farmer SR. Recruitment of brown adipose tissue as a therapy for obesity-associated diseases. Front Endocrinol (Lausanne) 3: 14, 2012.

10.  Cannon B, Nedergaard J. Thermogenesis challenges the adipostat hypothesis for body-weight control. Proc Nutr Soc. 2009 Nov;68(4):401-7. doi: 10.1017/S0029665109990255.

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