Mitochondrial uncouplers have recently garnered considerable attention in the development of drugs that target obesity and metabolic disease. Conceptually, this makes perfect sense, because metabolic dysfunction due to excess ectopic lipid deposition is a case of mismatched supply and demand. During cellular respiration, the electron transport chain establishes the mitochondrial membrane potential, which is required for protons to move through ATP synthase into the mitochondrial matrix (1). However, mitochondrial uncoupling dissipates the proton gradient. By reducing the efficiency of ATP synthesis, uncoupling ensures that more respiration occurs to provide the necessary ATP. Thus, by promoting mitochondrial oxidation, uncouplers can increase metabolic demand and thereby reduce lipid content in metabolically active tissues.

In this issue of Diabetes, Beretta et al. (2) introduce SHD865, a novel imidazolopyrazine uncoupler capable of reducing diet-induced obesity and improving glucose tolerance in mice without modifying food intake or lean mass. The authors expand on their previous results showcasing the effect of BAM15, a novel uncoupler from which SHD865 was derived, successfully improving diet-induced obesity and insulin sensitivity in mice (3). A safer derivative of BAM15, SHD865 represents a particularly promising mitochondrial uncoupler regarding its antiobesity effects. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and 2,4-dinitrophenol (DNP) are two classic uncouplers with therapeutic potential overshadowed by their risk of toxic side effects when not tissue (particularly liver) targeted. The authors’ development of BAM15 showed some potential to resolve these problems, but drawbacks remained in the drug’s half-life and aqueous solubility at high doses. In addition to addressing these concerns, SHD865 induced a lower maximal respiration rate than BAM15, which may bode well for its safety profile.

Recognizing the imbalance in calories consumed and used that underpins obesity, SHD865 targets energy expenditure and induces negative systemic energy balance. As the authors note, there are no U.S. Food and Drug Administration–approved antiobesity drugs with this focus. Possibly the most notable quality of SHD865 is its ability to maintain lean-mass body composition and food intake in mice while reducing adiposity. All of the currently available weight loss drugs target appetite, reducing the drive to eat or leaving patients with a sense of satiety that dampens their appetite and reduces food intake (4); the leading weight loss drugs are glucagon-like peptide 1 receptor agonists, which act as notable examples of this (5).

Additionally, Beretta et al. (2) found that SHD865 reduced expression of acetyl-CoA carboxylase and fatty acid synthase, two rate-limiting liver lipogenesis enzymes, which likely explains the drug’s ability to lower postprandial triglyceride and cholesterol concentrations in plasma. These data demonstrate that SHD865 may both reduce lipid accumulation and accelerate its clearance, representing one of the first instances in which uncouplers have been shown to prevent lipogenesis in addition to accelerating mitochondrial oxidation.

The authors’ findings have significant implications considering the various debilitating consequences of obesity. Obesity is widely recognized as the leading risk factor for type 2 diabetes, and it increases the likelihood of cardiovascular disease, depression, and worsened quality of life (68). The authors’ finding that SHD865 improved insulin sensitivity prompts future work into SHD865 as a potential treatment for type 2 diabetes that targets insulin resistance. Additionally, obesity has been established as a risk factor for the appearance and progression of various tumor types and has consistently been observed to worsen prognosis through increased risk of cancer development and progression (9,10). A DNP-based mitochondrial uncoupler was found to slow colon and breast cancer progression in mouse models (11,12), highlighting the exciting possibility that mitochondrial uncouplers such as SHD865 can intervene in the link between obesity and cancer.

Some uncoupling proteins, such as UC1 to UC3 and ANT1 to ANT4, may be involved in driving thermogenesis and, consequently, weight loss (1315). The expression of these proteins was not measured in this article, so future studies will be required to understand the effect of SHD865 on uncoupling protein expression. Additionally, as the authors note, future work using more extreme models, like those featuring genetic obesity, is necessary. Nonetheless, the promising results presented in Beretta et al. (2) certainly encourage further studies on imidazolopyrazine mitochondrial uncouplers as the future of safe and effective antiobesity drugs based on increasing energy expenditure, thereby targeting the root cause of obesity-associated metabolic dysfunction. SHD865 may exemplify the potential for a new class of mitochondrial uncouplers that could address the obesity epidemic along with its downstream consequences and comorbidities.

See accompanying article, p. 374.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

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