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Biosacetalin 1,1-Diethoxyethane enhances aerobic respiration via activation of AMP-activated protein kinase

ABSTRACT: The enzyme 5ʹ-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key regulator of cellular energy metabolism, playing a protective role in cardiovascular remodeling and diseases. Here, 1,1-Diethoxyethane (1,1-DEE), a compound traditionally known as a flavoring agent in wine and distilled spirits, was identified as an AMPK activator. By analyzing AC16 cardiomyocytes with the Seahorse Mito Stress Test, we found that 1,1-DEE induced a transient inhibition of both mitochondrial respiration and glycolysis, resulting in reduced ATP production. This metabolic disturbance triggered AMPK activation in a time- and concentration-dependent manner, leading to adaptive increases in the phosphorylation of acetyl-CoA carboxylase and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2, which promotes fatty acid oxidation and glycolysis. AMPK activation also enhanced mitochondrial biogenesis by upregulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha and mitochondrial transcription factor A. These alterations led to a sustained increase in both mitochondrial respiration and glycolysis. Overall, our findings unravel the important physiological role of 1,1-DEE in energy homeostasis through AMPK activation and aerobic respiration. This mechanism may hold therapeutic potential for the prevention and treatment of metabolic and cardiovascular diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE319948 | GEO | 2026/02/19

REPOSITORIES: GEO

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Project description:Type 2 diabetes (T2D) is a growing global health crisis, largely driven by rising obesity rates. Untreated T2D leads to severe complications such as cardiovascular disease, nephropathy, retinopathy, neuropathy, and hepatic dysfunction. Current therapies primarily manage hyperglycemia but often fail to address core pathophysiological drivers like insulin resistance and obesity. This highlights an urgent need for novel therapeutics with distinct mechanisms, particularly those targeting energy metabolism and insulin sensitivity, to improve long-term T2D outcomes. Modulating mitochondrial respiration through mild uncoupling has emerged as a promising strategy to promote negative energy balance. SR4, a small-molecule mitochondrial uncoupler, represents a novel class of fatty acid-activated proton transporters. In this study, we investigated the metabolic effects of oral SR4 administration in male db/db mice model of T2D. SR4 significantly reduced body weight gain and improved body composition by selectively decreasing fat mass without affecting lean mass. Indirect calorimetry confirmed that SR4 treatment increased oxygen consumption and total energy expenditure, independent of food intake. Importantly, SR4 substantially improved glycemic control, reduced insulin resistance, and prevented dyslipidemia, hepatic steatosis, and liver injury. Mechanistically, SR4 activated hepatic AMP-activated protein kinase (AMPK), enhanced mitochondrial respiration, and mitigated oxidative stress. Liver transcriptomic profiling further demonstrated broad metabolic reprogramming, including downregulation of lipogenesis and peroxisome proliferator-activated receptor γ (PPARγ) signaling, concurrently with upregulation of genes involved in energy metabolism and antioxidant defense. Collectively, these findings demonstrate that SR4 ameliorates multiple aspects of metabolic dysfunction in an obese T2D mouse model by targeting key pathways in energy regulation and lipid metabolism. Our results provide additional mechanistic insights into the effects of mitochondrial uncouplers in the liver and support further investigation of SR4 and related fatty acid anion transporters as a novel therapeutic class for metabolic diseases.

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Biosacetalin 1,1-Diethoxyethane enhances aerobic respiration via activation of AMP-activated protein kinase

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