On the other hand it has been proposed that that
On the other hand, it has been proposed that that BAT-dependent diet-induced thermogenesis greatly contributes to the maintenance of body weight. Thus, at thermoneutrality, in the absence of any thermal stress that requires of thermogenic processes to maintain body temperature, UCP1 knockout mice develop obesity [45,46]. However, BAT-dependent diet-induced remains a controversial issue [47,48] and some other mouse models exhibiting severe BAT thermogenesis deficiency due to lack of key genes involved in Dynasore metabolism, such as Esrra/Esrrg  or Cpt2 , do not develop obesity at thermoneutrality. Therefore, although it is conceivable to speculate that MTERF4-FAT-KO mice would develop obesity under thermoneutral conditions as a result of impaired thermogenesis induced by diet, such hypothesis would need to be corroborated in future studies.
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Introduction Diabetic nephropathy (DN) is the major microvascular complication of diabetes . Around 30% of diabetic patients finally progress to end-stage renal disease [2,3], which is characterized by glomerulosclerosis and inter-capillary glomerulonephritis with micro/macro-albuminuria [4,5]. Inflammation and oxidative stress are known as the major causes for the development of DN . Inflammatory cytokines, including interleukin 6 (IL6), tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β1) are elevated in plasma of patients with kidney disease . Kidney fibrosis is mostly preceded by and closely associated with chronic interstitial inflammation [, , ]. TGF-β1 is the primary factor that promotes fibrosis in chronic kidney disease [, , , ]. The activation of TGF-β1 or its downstream signaling pathways promotes extracellular matrix expansion leading to thickening of the basement membrane and glomerulosclerosis in the kidney . Toll like receptors (TLRs) mediate innate immune and inflammatory responses [, , , ]. TLR4 is an innate immune receptor classically activated by lipopolysaccharide in immune cells or by endogenous ligands (such as oxidized lipoproteins) in nonimmune cells [18,19]. TLR4 activates nuclear factor-κB (NF-κB), the master transcription factor controlling inflammatory genes. TLR4 expression increases in various cell types and organs of diabetic patients [16,20]. Some studies have indicated that stress-activated protein kinases of the mitogen activated protein kinase (MAPK) family, such as c-Jun N-terminal kinase (JNK) and p38, are associated with DN in human and rodent models . Therefore, the activation of NF-κB and MAPK may contribute to pathogenesis of DN [22,23]. Lysophosphatidic acid (LPA) is a small phospholipid derivative that acts as a potent mitogen through its G protein coupled receptors (LPAR1-6s) . The release of LPA mediates pro-inflammatory responses in several tissues including the kidney [25,26]. Recent studies have also shown that LPA is increased in the serum of human diabetic patients and kidney cortex of db/db mice [27,28], implicating it in diabetic kidney diseases. AM095 is an antagonist of the LPA type 1 receptor . It has been shown to inhibit LPA-induced chemotaxis in both mouse LPA1R over-expressed CHO cell lines and human A2058 melanoma cells. In addition, AM095 suppresses LPA-induced histamine release and reduces macrophage and lymphocyte infiltration in mice administered with bleomycin . These findings suggest that AM095 may be a potential therapeutic antagonist for blocking abnormally activated LPA signaling in the hyperglycemia condition, thereby reducing the inflammatory response of DN. However, it is not clear whether AM095 is effective in DN.
Materials and methods
Discussion Recent studies have indicated that LPARs antagonism improves renal dysfunction in type 2 diabetic models [32,35]. Here, we demonstrated that a LPAR1-specific antagonist, AM095, attenuates diabetic nephropathy in a type 1 diabetic model through suppressing directly and/or indirectly the ROS-mediated inflammatory response. We further suggested that TLR4 and TLR4-dependent NADPH oxidase play a critical role in the pathogenesis of DN by downregulating NF-κB and JNK signaling.