Renoprotective effects of brown adipose tissue activation in diabetic mice

Abstract

BackgroundBrown adipose tissue (BAT) has been regarded as a potential target organ to combat obesity and related metabolic disorders. However, the effect of BAT activation on the development of diabetic kidney disease (DKD) remains unclear.MethodsDiabetic mice were induced by streptozotocin (STZ) combined with a high‐fat diet. To activate BAT, mice were administered 1 mg/kg per day, i.p., CL316,243, a β3‐adrenergic receptor agonist, for 4 weeks. Blood glucose, serum lipids, adipokines, 24‐hour urinary albumin, 8‐hydroxydeoxyguanosine (8‐OHdG), and circulating microRNA (miRNA) levels were analyzed, in addition to renal pathology. Histological changes (fibrosis, inflammation) were evaluated in the kidneys, as was the expression of oxidative stress‐related genes. Renal signaling pathways (fibroblast growth factor [Fgf]21/β‐klotho/FGF receptor 1c and AMP‐activated protein kinase[AMPK]/sirtuin 1 [Sirt1]/peroxisome proliferator‐activated receptor‐γ coactivator‐1α [Pgc1α]) were also evaluated.ResultsCompared with untreated STZ‐diabetic mice, CL316,243 treatment reduced blood glucose, albeit not significantly (20.58 ± 3.55 vs 23.60 ± 3.90 mM), and significantly decreased triglycerides and low‐density lipoprotein cholesterol and increased high‐density lipoprotein cholesterol. Simultaneously, BAT activation significantly decreased 24‐hour urinary albumin (34.21 ± 6.28 vs 70.46 ± 15.81 μg/24 h; P < 0.05) and 8‐OHdG, improved renal fibrosis, inflammation, and oxidative stress, and ameliorated renal morphological abnormalities. In addition to enhancing BAT activity, CL316,243 significantly increased serum adiponectin concentrations and renal Fgf21 sensitivity, and reactivated the renal AMPK/Sirt1/Pgc1α signaling pathway. Furthermore, CL316,243 treatment increased levels of some circulating miRNAs and downregulated expression of their target genes in the kidney.ConclusionsActivating BAT could improve kidney injury in diabetic mice via metabolic improvements and renal AMPK activation by beneficial adipokines and miRNAs.

Transplantation of brown adipose tissue up-regulates miR-99a to ameliorate liver metabolic disorders in diabetic mice by targeting NOX4

“…Our previous study had also shown that activation of brown adipose tissue could significantly up-regulate the levels of serum miR-99a, miR-99b, miR-30b, miR-100, etc. [43]. Study by Thomou et al has shown that adipose tissue was the main source of circulating miRNAs and that the level of miR-99a and miR-99b in the circulation was significantly increased after BAT transplantation in a fat-specific knockout of the miRNA-processing enzyme Dicer mice [13].…”

Advances in understanding the role of adiponectin in renal fibrosis

“…Activation of the AMPK‐SIRT1‐PGC1α‐axis after the binding of APN to Adipo‐R1 inhibits NF‐κB and its downstream pathway, thereby significantly reducing the 24 hours urinary albumin level, preventing inflammation and oxidative stress, inhibiting the accumulation of renal ECM and ameliorating renal morphological abnormalities. This delays the progression of renal fibrosis in experimental animals 17 . In addition, study of a model of contrast‐induced nephropathy in Sprague‐Dawley rats reported that AdipoRon protected against contrast‐induced nephropathy via activation of the AMPK pathway, and also significantly reversed the pathological effects of contrast on serum creatinine, blood urea nitrogen and creatinine clearance level 18 …”

The Multiple Roles of Fibroblast Growth Factor in Diabetic Nephropathy

“…155 Therefore, over-whelming evidence shows that AMPK/ SIRT1 activation reduces renal inflammation, oxidative stress and podocyte apoptosis in DN patients, thus protecting against kidney damages. 156,157 AMPK and SIRT1 are downstream kinases for FGF21. Activation of AMPK stimulates glucose metabolism and oxidation of fatty acids in patients with diabetes mellitus.…”