Abstract Body (Do not enter title and authors here): Introduction: If prevention and treatment measures do not improve, the global economic impact of obesity will reach close to $4 trillion annually by 2035. At close to 3% of global GDP, this is comparable to the economic impact of COVID-19 in 2020. This makes identifying new therapeutic targets for preventing or treating obesity and associated health concerns imperative.
Overnutrition and obesity lead to the accumulation of lipids in our bodies. Among the lipids that accumulate, ceramides could be the most deleterious since pharmacological and genetic interventions that reduce ceramide production in rodents improve insulin sensitivity, resolve hepatic steatosis, and prevent atherosclerosis associated with obesity. However, the existing mechanisms for ceramide action cannot fully account for the broad spectrum of metabolic changes caused by ceramides.
Research Question: Are there mediators of ceramide action that could be targeted to improve metabolic homeostasis in obesity without altering ceramide levels?
Methods: We used comparative transcriptomic screens in adipose tissues from obese mice to identify ceramide-regulated genes. We used adeno-associated virus (AAV) to overexpress and Rosa26-CreER^T2 and Ucp1-CreER^T2 systems to delete the gene we identified in the whole body and UCP1⁺ thermogenic adipocytes, respectively. These overexpression and knockout mice were studied under diet-induced obesity and cold-exposure conditions to observe the effects on adipose tissue and whole-body energy and glucose homeostasis.
Results: We identified Bone Morphogenetic Protein 3 (Bmp3) as a ceramide-induced transcript in the adipose tissue. Systemic overexpression of Bmp3 exaggerated diet-induced obesity and associated insulin resistance in mice. Overexpression of Bmp3 also impaired diet and cold-induced thermogenesis. Whole-body deletion of Bmp3 protected from diet-induced obesity and insulin resistance. Deletion of Bmp3 in UCP1⁺ thermogenic adipocytes could recapitulate the effects of whole-body knockout, indicating that UCP1⁺ thermogenic adipocytes play a major role in eliciting the effects of BMP3. In humans, we found that higher BMP3 levels in circulation were positively associated with numerous metabolic traits of obesity and insulin resistance.
Conclusions: Inhibiting BMP3 can prevent and reverse the metabolic derangements associated with obesity, thus identifying BMP3 as a novel target for treating these conditions.