Insulin resistance and tubular energy metabolism during obesity-induced renal disease prior to puberty
Description: Childhood/prepubertal obesity (PPO) is increasing at an alarming rate and is now associated with the early development of renal disease. Despite this, mechanisms of obesity-induced renal disease (OIRD) in children have received little attention due to the lack of a suitable animal model. The obese Dahl salt-sensitive leptin receptor mutant rat (SSLepRmutant rat) is an animal model of obesity that develops progressive renal disease independent of hyperglycemia and hypertension prior to puberty. Therefore, the SSLepRmutant rat represents a novel, clinically relevant model to study the mechanisms of renal disease during PPO. Changes in tubular glucose and energy metabolism are now considered as major characteristics of renal disease. Recently, we observed that early development of renal injury in SSLepRmutant rats is associated with insulin resistance (IR), alterations in tubular metabolism and mitochondrial dysfunction. Insulin is a key anabolic hormone that controls almost every metabolic pathway either by promoting or inhibiting. Recent research shows that during diabetes IR leads to alterations in renal proximal tubular (PT) metabolism and cause mitochondrial dysfunction in adult patients. However, it is not known the effects of IR in kidney injury during childhood obesity without diabetes. Aim 1 of this grant will test the hypothesis that the inhibition of IR via time-restricted feeding (TRF) will prevent the early progression of OIRD. During diabetes, energy metabolism in the PT shifts, leading to increased glycolysis and gluconeogenesis (GNG), with a reduction in fatty acid oxidation (FAO). Interestingly, we have found that in SSLepRmutant rats during PPO, FAO is reduced and GNG is elevated, but glycolysis remains unchanged in the PT. Moreover, there is a significant increase in renal PT sodium glucose co-transporter 2 (SGLT2) expression along with mitochondrial dysfunction in SSLepRmutant rats. Therefore, Aim 2 will test the hypothesis that blocking SGLT2 will inhibit metabolic alteration and improve mitochondrial function and slow the early progression of OIRD. These proposed studies will identify therapeutic targets to reduce the early risk of renal disease and prevent the future risk of chronic kidney disease later in life in obese patients.
Funder: American Heart Association
Amount: $69,550
Funding type: training
Funder scheme: Predoctoral Fellowship
Start date: 2025-01-01
End date: 2026-12-31
Investigators: Sautan Mandal, Sautan Mandal
Institution: University of Mississippi Medical Center
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 1
Funder award ID: 25PRE1373476
OpenAlex ID: G219888529