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Obesity and type 2 diabetes have reached epidemic proportions globally, necessitating effective and sustainable treatment strategies. Weight loss, particularly through metabolic bariatric surgery (MBS), has shown promising outcomes in improving metabolic and kidney health. However, MBS is a complex and invasive procedure associated with risks and complications. By using molecular signatures, we aimed to discover intra-renal molecular pathways that could serve as pharmacological targets and alternatives to MBS.
We obtained single-cell data from five paired human research kidney biopsy samples, collected before and after MBS, to identify the suppressed genes post-surgery. Additionally, we utilized bulk kidney RNA-seq data from obese rats undergoing MBS (1). The overlapping genes found to be suppressed in both human kidney and rat renal data were included in the analysis using the Library of Integrated Network-Based Cellular Signatures (LINCS) database, with the HA1E cell line as the reference, to identify drugs exhibiting similar gene expression profiles to MBS.
(1) Martin WP, Chuah YHD, Abdelaal M, Pedersen A, Malmodin D, Abrahamsson S, Hutter M, Godson C, Brennan EP, Fändriks L, le Roux CW, Docherty NG. Medications Activating Tubular Fatty Acid Oxidation Enhance the Protective Effects of Roux-en-Y Gastric Bypass Surgery in a Rat Model of Early Diabetic Kidney Disease. Front Endocrinol (Lausanne). 2022 Jan 26;12:757228. doi: 10.3389/fendo.2021.757228. PMID: 35222262; PMCID: PMC8867227.
The comparison identified 14 classes of drugs that mimic the transcriptomics response to MBS (Fig.1). These transcriptional signatures align with previous studies that have demonstrated the therapeutic potential of these drug classes in addressing obesity and associated metabolic end-organ damage. The drug signature mapping forms a starting point for future investigations and potential clinical applications to enhance kidney health in obesity.
Figure 1: Identification of Candidate Drugs Mimicking Molecular Changes Post-Surgery. A) Venn Diagram: the overlap of suppressed genes following metabolic bariatric surgery (MSG) surgery in kidney biopsies of youth type 2 diabetes patients and in the kidney cortex of post-MSG in an obese rat model. The shared region represents the genes that exhibit downregulation in both species, indicating common molecular alterations induced by these surgical interventions. B) Drug Categories: The drug categories identified in an in vitro screen (LINCS) to replicate transcriptional changes seen in the in vivo studies. These drug classes have the potential to replicate elements of the metabolic benefits associated with MSG surgery in both human patients and rats.
The wide spectrum of mode of action of drugs mapping to the MBS signatures that can replicate the benefits of MBS offers additional treatment strategies for obesity and type 2 diabetes. The next step involves validating these drugs in a rat model to further establish their therapeutic potential and safety profiles in vivo, moving closer to clinical translation.