As part of traditional Chinese medication regimens, cordyceps extract has previously been shown to ameliorate various diseases, including metabolic anomalies. However, it needs to be clarified what the bioactive ingredient in cordyceps extracts is and the molecular mechanisms through which these extracts elicit beneficial effects. Here we demonstrate that myriocin, a pharmacological inhibitor of ceramide biosynthesis in cordyceps extract, is critical for its beneficial metabolic effects.

We further demonstrate that treating mice with cordyceps extract containing myriocin at a currently recommended dose of cordyceps for human consumption reduces ceramide biosynthesis, alters gut microbial ecology, and has profound effects on increasing energy expenditure, insulin sensitivity, and resolving hepatic steatosis.

Ceramides accrue in obesity, and recent studies from us and others suggest that these are toxic lipid metabolites that cause insulin resistance. Moreover, our recent studies have indicated that ceramides are key nutrient signals that regulate energy storage and utilization.

Furthermore, inhibition of ceramide biosynthesis using myriocin in rodents improves various features of metabolic diseases such as insulin sensitivity, hepatic steatosis, and cardiovascular complications. Given the beneficial effects elicited by the inhibition of ceramide biosynthesis, targeting the ceramide biosynthetic pathway offers a novel strategy for treating obesity and associated comorbidities.

Despite this wealth of knowledge in rodents and other mammals, the literature lacks any ceramide intervention studies that include human myriocin usage. However, cordyceps extracts, a fungi species from which myriocin was originally extracted, have been used in traditional Asian medicines for centuries for multiple indications, including diabetes.

The present study identified some of the naturally occurring or artificially grown and readily available cordyceps extracts that contain myriocin and suggested that a substantial number of individuals might already be consuming these myriocin-enriched extracts, perhaps benefiting from the inhibition of ceramide biosynthesis. Future human intervention studies are highly warranted to determine whether myriocin-containing cordyceps extract inhibits ceramide biosynthesis and alters glucose and energy metabolism.

Systemic inhibition of ceramide biosynthesis increases energy expenditure by elevating adipose tissue thermogenic program and improves glucose uptake and metabolism by regulating Akt/PKB activation. We identify that cordyceps extract elicits its beneficial effects by elevating the thermogenic program in adipose tissue and glucose uptake and metabolism via regulation of Akt/PKB activation. Inhibition of ceramide biosynthesis using cordyceps extract inhibits numerous sphingolipids, including sphingomyelin, that would argue whether observed improvements are due to ceramides or another sphingolipid intermediate. Given that ceramides but no other sphingolipids modulate thermogenic program in adipocytes and Akt/PKB activation, we think these improvements were driven by exclusive inhibition of ceramides but no other sphingolipids.

Surprisingly, another sample does not contain myriocin, induces ceramide accumulation, and ensues negative metabolic effects associated with ceramide accumulation, such as decreases in energy expenditure and increases in body and liver weight. Moreover, these data indicate that additional screening procedures should be implemented to ensure that commercially available cordyceps extracts are safe without adverse effects.

In addition to the known mechanisms of ceramide action, the present study identifies alterations in gut microbiota composition following ceramide inhibition. It identifies two genera, Clostridium and Bilophila, as the key microbes that are altered following ceramide inhibition and were found to be correlated with either body weight, fat mass, and fasting blood glucose or fed blood glucose.

Though we identified beneficial microbial changes that potentially influence systemic metabolism, we cannot determine whether these changes are secondary to a healthier gut resulting from ceramide inhibition. Therefore, future studies will explore whether these microbes contribute to some beneficial metabolic homeostasis attributed to ceramide inhibition.

Notably, therapeutically targeting serine palmitoyl transferase (SPT), the first enzyme in the synthetic ceramide pathway, hit a roadblock as genetically ablating SPT presents with lethality. These effects are accounted for by ceramides’ requirement to maintain intestinal homeostasis. Similarly, pharmacological inhibition of SPT, with a new class of compounds, results in intestinal toxicity.

Despite these limitations, numerous studies have repeatedly shown the robust efficacy of myriocin in inhibiting SPT activity, reducing ceramide biosynthesis, and resolving various metabolic indices. The toxicity associated with SPT inhibition results from complete inhibition of SPT, as mice lacking only one allele of SPT are viable without any major developmental effects and exhibit reductions in ceramide accrual and improvements in insulin sensitivity. Similarly, a high dosage of cordyceps containing myriocin induces intestinal toxicity compared to a lower dose.

Therefore, the low dosage of cordyceps containing myriocin similar to the one tested in this study, which has been consumed for centuries, might provide a therapeutic opportunity to safely inhibit SPT, reduce ceramide accumulation and improve insulin sensitivity. Moreover, purified low-dose myriocin that inhibits ceramide biosynthesis without eliciting intestinal toxicity might present an alternative strategy to inhibit ceramide biosynthesis and improve human metabolic indices.

Collectively, we identify that various commercially and readily available cordyceps extracts currently consumed by humans contain ceramide inhibitor myriocin and provide proof-of-principle studies that inhibition of ceramide biosynthesis with cordyceps extract containing myriocin might be a readily available therapeutic option for the treatment of metabolic diseases.

Moreover, given that cordyceps extract has been thoroughly examined for not inducing mutagenicity and has been assigned as one of the safest supplements, these supplements might offer first-in-class ceramide intervention drugs for treating metabolic diseases.