Multi-Omic Characterisation of Renal Responses to Intentional Weight Loss in Diabetic Kidney Disease

Metabolic/bariatric surgery reduces the incidence of albuminuria and slows chronic kidney disease progression over extended follow-up, and hence may have a potential role to play as a complement to medical therapy in the management of diabetic kidney disease (DKD). Enhanced understanding of the molecular underpinnings of surgery-associated renoprotection, its reliance on weight loss, and synergy with medical treatment may also identify new algorithms and treatment targets to improve control of DKD. In a sub-study of the Microvascular Outcomes after Metabolic Surgery randomised clinical trial, I characterised urinary metabolomic changes by proton nuclear magnetic resonance (1H-NMR) spectroscopy at baseline and six months following randomisation to medical therapy alone (MTA) and combined metabolic surgery plus medical therapy (CSM). Roux-en-Y gastric bypass (RYGB) was the metabolic surgery employed. Whilst CSM and MTA both reduced urinary excretion of sugars, CSM generated a distinctive urinary metabolomic profile characterised by increases in host-microbial co-metabolites (N-phenylacetylglycine, trimethylamine N-oxide, and 4-aminobutyrate/GABA) and amino acids (arginine and glutamine). Furthermore, reductions in aromatic amino acids (phenylalanine and tyrosine), as well as branched-chain amino acids and related catabolites (valine, leucine, 3-hydroxyisobutyrate, 3-hydroxyisovalerate, and 3-methyl-2-oxovalerate), were observed following CSM but not MTA. Urinary metabolites changed by CSM at six months were moderately-to-strongly correlated with improvements in cardiometabolic and renal indices up to 24 months following treatment initiation. In the Zucker Diabetic Sprague Dawley (ZDSD) rat model of DKD, I compared the effects of RYGB surgery alone and in combination with fenofibrate, metformin, ramipril, and rosuvastatin (RYGB-FMRR) on renal injury, the renal cortical transcriptome, and the urinary 1H-NMR metabolome. RYGB-FMRR was superior to RYGB alone with respect to metabolic control, albuminuria, and histological and ultrastructural indices of glomerular damage and mitochondrial injury in the proximal tubule. Fenofibrate exerted a dominant effect on gene expression changes following RYGB-FMRR, and led to the transcriptional induction of peroxisome proliferator-activated receptor-alpha (PPARa)-responsive genes that are predominantly expressed in the proximal tubule and which regulate peroxisomal and mitochondrial fatty acid oxidation (FAO). In the aforementioned ZDSD model as well as the Zucker Diabetic Fatty (ZDF) rat model, the effects on renal injury as well as the renal cortical transcriptome of a non-invasive intervention designed to mimic RYGB were explored. This intervention, entitled dietary restriction plus medical therapy (DMT), consisted of dietary restriction to 20% weight loss (comparable to RYGB surgery) plus treatment with fenofibrate, liraglutide, metformin, ramipril, and rosuvastatin. Changes in the urinary 1H-NMR metabolome were also profiled in the ZDSD model. DMT improved metabolic control, albuminuria, and histological and ultrastructural indices of glomerular injury in both animal models. Similar to changes observed after RYGB-FMRR, transcriptomic evidence of increased PPARa-regulated FAO was observed in both ZDF and ZDSD rats after DMT. PPARa-regulated renal FAO transcripts and related urinary nicotinamide metabolites and TCA cycle intermediates were moderately-to-strongly correlated with improvements in glomerular and proximal tubular injury following both RYGB-FMRR and DMT. Integrative multi-omic analyses point to PPARa-stimulated FAO in the proximal tubule as a dominant effector of treatment response when surgical or diet-induced weight loss is combined with medical therapy in experimental DKD. Synergism between intentional weight loss and pharmacological stimulation of FAO represents a promising combinatorial approach to the treatment of DKD in the setting of obesity.