Abstract
Recent studies suggested that renal gluconeogenesis is substantially stimulated in the kidney in presence of obesity. However, the mechanisms responsible for such stimulation are not well understood. Recently, our laboratory demonstrated that mice fed high fat diet (HFD) exhibited increase in renal Atp6ap2 [also known as (Pro)renin receptor] expression. We hypothesized that HFD upregulates renal gluconeogenesis via Atp6ap2-PGC-1α and AKT pathway. Using real-time polymerase chain reaction, western blot analysis and immunostaining, we evaluated renal expression of the Atp6ap2 and renal gluconeogenic enzymes, PEPCK and G6Pase, in wild type and inducible nephron specific Atp6ap2 knockout mice fed normal diet (ND, 12 kcal% fat) or a high-fat diet (HFD, 45 kcal% fat) for 8 weeks. Compared with ND, HFD mice had significantly higher body weight (23%) (P < 0.05), renal mRNA and protein expression of Atp6ap2 (39 and 35%), PEPCK (44 and 125%) and G6Pase (39 and 44%) respectively. In addition, compared to ND, HFD mice had increased renal protein expression of PGC-1α by 32% (P < 0.05) and downregulated AKT by 33% (P < 0.05) respectively in renal cortex. Atp6ap2-KO abrogated these changes in the mice fed HFD. In conclusion, we identified novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway.
Highlights
Recent studies suggested that renal gluconeogenesis is substantially stimulated in the kidney in presence of obesity
Impairment in the PI3K/AKT pathway is associated with glucose intolerance and insulin resistance along with increased expression of gluconeogenic enzymes[9,10] enhancement of the PI3K/AKT activities may be a promising strategy for improving glucose tolerance and insulin sensitivity
We evaluated the renal gluconeogenic enzymes to determine whether gluconeogenesis is enhanced during high fat diet (HFD) intake and whether it is dependent on Atp6ap[2]
Summary
Recent studies suggested that renal gluconeogenesis is substantially stimulated in the kidney in presence of obesity. Our laboratory demonstrated that mice fed high fat diet (HFD) exhibited increase in renal Atp6ap2 [ known as (Pro)renin receptor] expression. We identified novel regulation of renal gluconeogenesis by Atp6ap[2] in response to high fat diet via PGC1-α/AKT-1 pathway. We reported that renal Atp6ap[2] expression is upregulated in high-fat diet and in d iabetes[14,15,16]. The kidney has been known to play an important role in systemic glucose homeostasis, the mechanisms involved in the regulation of gluconeogenesis in the kidney remain poorly understood. Based on previous observations and lack of clear understanding, our study aimed to determine the relationship of Atp6ap[2] and renal gluconeogenesis in normal and high-fat diet (HFD)-induced obesity in mice. We tested the hypothesis that HFD upregulates renal gluconeogenesis via Atp6ap2-PGC-1α and AKT signaling cascade
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