Mitochondrial Uncouplers: The Future of Weight Loss Medications?

January 16, 2025

Clinical Questions Endocrine 6 min read

By Ella Feiner

Peer Reviewed

In a world abundant with food and sedentary lifestyles, the global prevalence of cardiometabolic disease has reached alarming levels. Nearly half of Americans grapple with conditions such as diabetes, heart failure, non-alcoholic fatty liver disease (NAFLD), and chronic kidney disease.1 Moreover, the inflammatory state associated with obesity has been linked to an increased risk of diseases like cancer2 and dementia.3 The unmet need for effective therapies in the realm of metabolic health has sparked a wave of innovation in recent years, with pharmaceutical companies racing to develop drugs that not only tackle obesity but also mitigate its associated health risks.

In recent years, advancements in medical approaches to cardiometabolic disease led to the development of glucagon-like peptide (GLP), glucose-dependent insulinotropic peptide (GIP), and glucagon agonists. These medications work via the incretin pathway, a key hormonal axis involved in regulating blood glucose. Initially developed for type 2 diabetes, researchers soon noted that these drugs not only improved glycemic control but also caused early satiety and promoted weight loss,4 likely by modulating appetite signals in the central nervous system.5 In the eight years since this discovery, incretin mimetics have been widely adopted for weight loss, creating a market worth billions of dollars.6 Ongoing research suggests that these medications also help patients with other cardiometabolic diseases such as heart failure7 and NAFLD.8

However, while these drugs have proven to be efficacious, they have the potential to cause many adverse effects. They are commonly associated with nausea, vomiting, biliary disease, pancreatitis, and small bowel obstruction, likely due to the mechanism of delayed gastric emptying.9 But most concerningly, through their effects on the incretin pathway, these medications cause a loss of both adipose tissue and lean body mass.10

Clinical trials evaluating weight loss tend to focus on total weight lost, while ignoring effects on body composition. However, research demonstrates that the main driver of cardiometabolic disease is the accumulation of visceral fat, or fat surrounding vital organs.11 Lean mass, which includes both muscle and bone, is critical for preventing frailty, maintaining the metabolic rate after weight loss, and decreasing mortality.12 Unfortunately, the 2021 STEP 1 trial of semaglutide demonstrated that 39% of total weight lost was lean mass.13 While we lack long-term data on these drugs, the physiologic role of lean body mass in metabolic health suggests that a loss of muscle and bone could lead to harm for patients as they age. Physicians are combating this problem by encouraging patients to maintain adequate protein intake,14 incorporate resistance training, and even combine incretin agonists with muscle-building agents,15 but the nonselective loss of both fat and lean body mass remains a fundamental flaw in this class of medications.

The ideal weight loss medication is a drug that selectively targets adipose tissue while preserving lean body mass and metabolic health. Researchers have recently studied a class of compounds known as mitochondrial uncouplers that may achieve just that.16 By disrupting cellular metabolism, these drugs may potentially induce fat loss alone.

To understand mitochondrial uncouplers, let us first review the physiology of normal metabolism. In a healthy human cell, adenosine triphosphate (ATP) production occurs through oxidative phosphorylation, a complex biochemical pathway that harnesses energy derived from the oxidation of nutrients like glucose and fatty acids. This process involves a series of protein complexes embedded in the inner mitochondrial membrane (IMM), collectively known as the electron transport chain (ETC). As electrons are shuttled along the ETC, a proton gradient is established across the IMM, driving the generation of ATP by the enzyme ATP synthase.17

Mitochondrial uncouplers fundamentally alter the efficiency of this process. They act as protonophores, facilitating the transport of protons across the IMM and effectively “uncoupling” electron transport from ATP synthesis.18 Imagine the mitochondria as a hydroelectric dam, with the proton gradient serving as a reservoir of potential energy. Under normal conditions, the flow of protons through ATP synthase is akin to water flowing through a turbine, generating ATP. Mitochondrial uncouplers create a “leak” in the dam, allowing protons to bypass ATP synthase and escape as heat. This uncoupling of electron transport from ATP synthesis effectively short-circuits cellular metabolism, leading to increased calorie expenditure and heat production. In other words, more nutrients are oxidized to create the same amount of ATP, promoting fat oxidation and enhancing the metabolic rate.

Although mitochondrial uncouplers have been studied for nearly a century, their clinical potential was historically limited by narrow therapeutic windows and life-threatening toxicity. However, recent advancements in tissue targeting and safe dosing have revitalized interest in this approach. The biotech company Rivus Pharmaceuticals (Charlottesville, VA) has developed an artificial intelligence-based drug discovery platform to identify novel small molecule cardiometabolic accelerators.19 Their lead asset, HU6, is a small molecule that is hepatically metabolized to 2,4-dinitrophenol (2,4-DNP), a well-known mitochondrial uncoupler that increases substrate utilization in the liver.20

2,4-DNP was initially marketed in the 1930s and led to significant weight loss, but high peak concentrations of the drug led to dangerous adverse effects like hyperthermia.21 Using the precursor metabolite HU6 mitigates these effects by minimizing rapid absorption and reducing the peak concentrations necessary to achieve sufficient liver exposure, creating a wider therapeutic index while maintaining efficacy.20 A recently completed phase 2a randomized controlled trial in 506 patients with NAFLD and BMI 28-45 kg/m2  demonstrated that HU6 450 mg PO daily for 61 days led to a mean reduction in liver fat content of 33% without any serious adverse events.20 Encouragingly, the drug also induced overall body fat loss with no statistically significant loss of lean body mass.20

As the pharmaceutical industry continues to invest in innovative approaches to weight management, mitochondrial uncouplers have emerged as a promising class of medications that target fat loss while preserving muscle and bone. Further studies are required before these medications are ready for the clinic, but the progress made thus far by Rivus Pharmaceuticals represents an exciting area of drug development. Through continued research and clinical validation, these agents may represent the next frontier in the fight against obesity and its associated comorbidities.

Ella Feiner is a Class of 2026 medical student at NYU Grossman School of Medicine

Reviewed by Michael Tanner, MD, Executive Editor, Clinical Correlations

Image courtesy of Wikimedia Commons, source: https://commons.wikimedia.org/w/index.php?search=wegovy&title=Special:MediaSearch&go=Go&type=image

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