Research group Our main research focus is to unravel molecular mechanisms regulating glucose homeostasis and β-cell function in the context of diabetes and obesity. We are also analyzing the molecular mechanisms by which the compound O304/ATX-304, a mitochondrial uncoupler and indirect activator of AMPK ameliorates obesity and diabetes as well as restores β-cell function.
The global increase in obesity and diabetes over recent decades constitutes a major health threat and has also led to a rise in associated diseases such as cardiovascular disease, kidney disease, and certain types of cancer. Perhaps less well known is that obesity and diabetes are also linked to mental health problems such as anxiety and depression; for example, depression is twice as common in individuals with obesity compared with those of a healthy weight. Exercise and dietary interventions are the first-line treatment recommendations for obesity and type 2 diabetes (T2D), but long-term adherence is challenging, and for some patients physical activity and dietary changes are insufficient or not feasible options. Exercise is also used as a treatment option for many patients with depression, and although the underlying mechanism(s) are not fully understood, studies have shown that exercise stimulates the formation of a tryptophan metabolite, KynA, which counteracts depression.
We have previously identified an indirect AMPK activator, termed O304/ATX-304, and demonstrated that it counteracts obesity- and age-related diabetes as well as cardiovascular dysfunction. We have shown that O304/ATX-304, similar to exercise, stimulates glucose uptake and metabolism in skeletal muscle and heart while preventing glycogen accumulation. These findings, together with our previous results showing that O304/ATX-304 can counteract and reverse obesity in mice by increasing energy expenditure, indicate that O304/ATX-304 induces a metabolic demand that drives glucose uptake and energy expenditure. Our recent findings demonstrate that O304/ATX-304 acts as a mild mitochondrial uncoupler, which is consistent with the beneficial effects of O304/ATX-304 on glucose uptake, glucose turnover, and increased energy expenditure. Our current studies focus on elucidating the molecular mechanisms by which O304/ATX-304 counteracts diabetes and obesity, and on determining whether O304/ATX-304, like exercise, can also prevent and/or alleviate obesity- and diabetes-associated depression.
