Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss

Abstract

New appetite-regulating antiobesity treatments such as semaglutide and agents under investigation such as tirzepatide show promise in achieving weight loss of 15% or more. Energy expenditure, fat oxidation, and lean mass preservation are important determinants of weight loss and weight-loss maintenance beyond appetite regulation. This review discusses prior failures in clinical development of weight-loss drugs targeting energy expenditure and explores novel strategies for targeting energy expenditure: mitochondrial proton leak, uncoupling, dynamics, and biogenesis; futile calcium and substrate cycling; leptin for weight maintenance; increased sympathetic nervous system activity; and browning of white fat. Relevant targets for preserving lean mass are also reviewed: growth hormone, activin type II receptor inhibition, and urocortin 2 and 3. We endorse moderate modulation of energy expenditure and preservation of lean mass in combination with efficient appetite reduction as a means of obtaining a significant, safe, and long-lasting weight loss. Furthermore, we suggest that the regulatory guidelines should be revisited to focus more on the quality of weight loss and its maintenance rather than the absolute weight loss. Commitment to this research focus both from a scientific and from a regulatory point of view could signal the beginning of the next era in obesity therapies.

FIGURE 1

Short‐term substrate balance in response to perturbation of energy balance. Most of the energy reserves in the body are stored in the form of fat, whereas protein represents some stores while only a small fraction of energy reserves is stored as carbohydrates (left panel). In a state of energy balance, the daily turnover (intake and oxidation) of carbohydrates represents approximately 50% to 100% of the body carbohydrate stores (circulating glucose plus liver and muscle glycogen), whereas protein and fat turnovers typically represent approximately 1% of body reserves. Changes in daily carbohydrate and protein intakes are rapidly mirrored by proportional changes in their respective oxidation, whereas changes in fat intake are not compensated in the short term by changes in fat oxidation. Therefore, both carbohydrate and protein balances are tightly maintained in response to changes in energy intake (right panel). In contrast, a surplus or a deficit in energy intake will be buffered by changes in fat stores: a loss in case of energy restriction and a gain during a surplus in energy intake. Adapted from Flatt (163) and Abbott et al. (5)

FIGURE 2

Long‐term change in body composition during sustained energy restriction. Body fat percentage is commonly higher than 25% in men with obesity and higher than 35% in women with obesity, and it increases with age. However, in many patients with severe obesity, fat mass can be up to 50% or more (left panel). The rest of the body (fat‐free mass) includes bone mass (3%‐5% body weight) and lean mass (with water). Lean mass is composed of large organs (including brain, liver, kidneys, and heart, 3%‐5% body weight), muscle mass (20%‐30%), and residual lean mass (digestive tract, small organs, connective tissue, tendons, etc.). In response to sustained energy restriction, most of the weight loss comes from loss of fat mass (60%‐85%) whereas 15% to 40% can come from a loss of lean mass. Most of the lost lean mass is a loss of skeletal muscle mass while other highly thermogenic organs, such as the liver, kidneys, and heart, are minimally impacted during weight loss (right panel). In addition, a small decrease in the residual lean mass (tendons, connective tissue, digestive tract, etc.) is also observed. Ideal pharmaceutical therapeutics for weight management should aim at preventing the decrease in lean mass, thus facilitating further loss of fat mass and weight‐loss maintenance

FIGURE 3

Weight‐loss trajectories with current and future therapies. Lifestyle interventions produce modest weight loss followed by weight regain. Most current pharmacotherapies induce additional but still insufficient weight loss, and weight regain typically occurs over time. RYGB is associated with substantially greater and more sustained weight loss, but nevertheless, some weight regain is observed after 2 years, and this therapy is not available for the majority of people living with obesity. The future of weight management must target not only weight loss but also quality of the weight loss and weight maintenance. To do that, medications must have effects beyond appetite suppression and must target preservation of lean mass and energy expenditure. RYGB, Roux‐en‐Y gastric bypass

FIGURE 4

Trends in energy balance regulation in response to different weight‐loss regimens. Energy intake and energy expenditure are balanced in weight‐stable obesity. (A) The reduction in energy intake during calorie restriction results in increased hunger and decreased satiation, driven by the neurohormonal mechanisms shown in the insert. Furthermore, energy expenditure decreases because of changes in body mass/lean mass, neurohormonal changes, and metabolic adaptation. Together, the increased hunger, decreased satiation, and decreased energy expenditure can readily promote weight regain, and the decrease in energy expenditure has been shown in some cases to persist for years (37). (B) When the weight loss is induced by continuous treatment with an appetite‐reducing compound, the hunger is decreased and the satiation is increased, enabling a longer period with reduced energy intake. However, energy expenditure is typically still reduced owing to loss of body mass/lean mass, neurohormonal changes, and some degree of metabolic adaptation. Consequently, the reduction in body weight is still limited, and usually, over time, weight regain occurs despite continued treatment, albeit at a slower rate compared with the regain observed with calorie restriction in panel A. (C) The future aspiration for pharmacotherapy that combines appetite‐reducing, energy‐expenditure–boosting, and lean‐mass–preserving mechanisms. Such a combination will decrease hunger, increase satiety, and protect lean mass, resulting in less suppression of energy expenditure, which (together with an actual energy‐expenditure–boosting component) will have the potential to cause greater and more sustainable weight loss. BMR, basal metabolic rate; CCK, cholecystokinin; EE, energy expenditure; EI, energy intake; GLP‐1, glucagon‐like peptide‐1; PYY, peptide YY; SNS, sympathetic nervous system; TEF, thermic effect of food; TH, thyroid hormone; WL, weight loss; WM, weight maintenance

FIGURE 5

Rethinking approaches for weight maintenance by targeting energy expenditure and lean mass preservation. Potential ways of maintaining or increasing energy expenditure include a diversity of targets ranging from sympathetic nervous system and transient receptor potential channel activation over browning of white adipose tissue to increased nonshivering thermogenesis in various organs. Nonshivering thermogenesis in skeletal muscle and other tissues can be brought about by increasing mitochondrial proton leak, by pharmacologically induced futile calcium cycling or various other futile substrate cycles, all of which would increase fatty acid oxidation and energy expenditure. Mitochondrial biogenesis and improved mitochondrial function are needed to support this increased energy demand. Potential targets for maintaining or increasing muscle mass include growth hormone, activin type II receptors A/B, and urocortin 2 and 3, which will secondarily lead to maintenance of the energy expenditure. ActIIR A/B, activin type II receptors A/B; AMPK, AMP‐activated protein kinase; FAO, fatty acid oxidation; GH, growth hormone; MFN2, mitofusin 2; N‐ADA, N‐arachidonoyl dopamine; PGC1α, peroxisome proliferator‐activated receptor gamma coactivator 1α; PPARα, peroxisome proliferator‐activated receptor alpha; RyR, ryanodine receptor; SERCA, sarcoplasmic/endoplasmic reticulum Ca2⁺‐dependent ATPase; SLN, sarcolipin; SNS, sympathetic nervous system; SR, sarcoplasmic reticulum; TRP, transient receptor potential; Ucn2/3, urocortin 2 and 3; UCP1, uncoupling protein 1; WAT, white adipose tissue