The present study evaluated the Telmisartan (TEL) efficacy on improving NAFLD in obese mice by modulating resistin, TRL4, and Myd88 inflammatory signaling expression. Despite all the advances in NAFLD/NASH pathophysiology, it is important to emphasize that until today there is no consolidated pharmacological treatment for this hepatic condition, especially considering evidence-based medicine protocols .
The main results of the present study showed that TEL effectively protects obese mice against NAFLD and ameliorates several metabolic parameters. The results are in consonance with previous studies which pointed to TEL as the most promising ARB for NAFLD treatment in terms of both safety and efficacy . The pathological changes found in NAFLD may help to understand these findings considering that this hepatic disorder is associated with the renin-angiotensin-system (RAS) inflammatory arm activation . NAFLD is commonly linked to obesity and insulin resistance, which leads to liver fat import and export imbalance . Other relevant cytokines are altered producing an imbalance between pro- and antioxidant actions and pro- and anti-inflammatory effects, which may contribute to the NAFLD progression to aggravated liver disease such as NASH and fibrosis .
The present data demonstrated that HFD mice present a worse glucose profile when compared with ST animals, with a lower glucose tolerance, which was significantly improved by TEL treatment. Concerning insulin sensitivity, a similar tendency was observed despite no statistical significance, which might be explained by the relatively short experiment duration.
The renin-angiotensin system (RAS) has been faced as a two-arms balance with opposite effects on the body composition. Several disease processes are able to unbalance this system. The ACE2/Ang-(1–7)/Mas axis is the antagonist arm with protective effects counteracting the deleterious effects of ACE/Ang II/AT1R axis excessive activation . Evidence suggests that obesity activates the inflammatory RAS arm composed (ACE/Ang II/AT1R)  pointing to Angiotensin II (Ang II) as a key piece in the abnormal hepatic lipid metabolism observed in NAFLD , which modifies intracellular insulin signaling by several mechanisms that ultimately result in worsening of insulin resistance. Ang II also induces the generation of reactive oxygen species (ROS), that initiates and propagates the pro-inflammatory mediator’s production, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and plasminogen activator inhibitor-1 (PAI-1), resulting in inflammation and additional impairment of insulin signaling, creating a vicious cycle of steatosis, necroinflammation, and fibrosis . On the other hand, increasing evidence has shown the beneficial effects of the ACE2/Ang-(1-7)/Mas axis on liver function and metabolism, with an important anti-obesity role in improving insulin sensitivity, glucose tolerance, and type 2 diabetes; modulating body fat; increasing adiponectin production; and reverting hyperleptinemia [32, 36].
Concerning AT1R-independent effects, it is important to emphasize the relationship between TEL and peroxisome proliferator-activated receptor gamma (PPAR-γ) activation. The nuclear PPARγ receptor is a transcription factor that regulates genes related to adipogenesis, lipid metabolism, and insulin sensitivity. TEL, unlike other ARBs, can work as a partial agonist of PPAR-γ , increasing insulin sensitivity, high-density lipoprotein levels, and decreasing inflammation, oxidative stress, cell proliferation, migration, fatty acid, and triglyceride levels. This effect occurs without the side effect of liquid retention produced by full PPAR-γ agonists such as pioglitazone or rosiglitazone .
TEL not only modulates RAS in order to inhibit AngII/AT1R deleterious effects, but also increases the activity of ACE2/Ang-(1-7)/Mas arm , beyond its PPAR-γ partial agonistic effects  and has been consistently proven to reduce insulin resistance . We demonstrated a significant improvement in liver size and hepatic lipid droplet infiltration in the HFD group treated with TEL, in accordance with previous studies . The morphological findings were positively correlated with the liver ultrasound (US) exam on the day before the sacrifice. Ultrasound was effective in demonstrating a higher liver size in the HFD group and a substantial decrease in this parameter when the HFD animals were treated with TEL. Also, US analysis of liver echogenicity showed elevated mean gray values in the HFD group, with a significant reduction of this parameter after TEL treatment in the HFD+TEL group. As in humans, hepatic steatosis in rodents is classically described on US as a diffuse increase in hepatic echogenicity, or “bright liver,” due to increased reflection of US from the liver parenchyma, which is caused by intracellular accumulation of fat vacuoles . Another parameter, such as reduced visualization of the diaphragm and of small peripheral vessels, with no changes in the liver surface, can also be utilized .
We also demonstrated that TEL reduces the adiposity and the mesenteric and epididymal adipose tissue weights in the HFD+TEL group when compared with the HDF group. Liao et al.  used measurements of epididymal fat pad thickness echography to successfully access the amount of this adipose tissue deposition. Kudo et al.  showed for the first time that TEL decreases the adipocyte size and upregulates the adiponectin secretion without affecting food intake in a murine NASH model, reducing the accumulation of visceral fat. Moreover, TEL but not the ARB Valsartan, increased the expression of both nuclear-encoded and mitochondrial-encoded genes in the skeletal muscle known to play important roles in mitochondrial energy metabolism.
Thus, in addition to a class effect of ARBs in modulating adipocyte size, the present findings raise the possibility that TEL may have a particularly strong impact on fat cell volume and fat accumulation and stand out in its metabolic effects, which may help to protect against dietary-induced visceral obesity and weight gain. The efficacy of TEL in reducing visceral fat mass may be relevant for patients since an increase in visceral fat is related to hypertension, dyslipidemia, and an impaired metabolic pattern, but also works as an independent predictor of mortality in humans .
Telmisartan effectively reduced liver expression of the pro-inflammatory resistin/TRL4/MYD88 pathway in HFD animals. Resistin is an important adipokine in an obesity setting and is positively correlated with increased fat mass and with a proinflammatory state, as reported in chronic liver diseases . Resistin modulates the synthesis and secretion of essential proinflammatory cytokines such as TNF-α and IL-6 by an NF-κB-dependent pathway . Santos et al.  showed that rats with HFD-induced obesity presented increased hepatic expression of resistin/TRL4/MAPK/NF-KB pathway developing insulin resistance, glucose intolerance, hyperinsulinemia, and dyslipidemia.
Toll-like receptors (TRLs) are expressed in immune cells and works in the immunological response to microbial agents. The activation of TRLs induces antimicrobial pathways of the innate defense, upregulation of antigen-presentation molecules, and secretion of cytokines that influence adaptive immune response. Inappropriate activation of TRL pathways by endogenous or exogenous ligands may lead to the initiation and/or perpetuation of autoimmune responses and tissue damage . It has recently been reported that the TRL4 signaling pathway plays an important role in the progression of hepatic inflammation and fibrosis. This effect occurs by triggering the expression of proinflammatory cytokines through mydd88-dependent activation that in turn is mediated by interleukin receptor-associated kinase IL-1 (IRAK), factor 6 associated with tumor necrosis factor receptor (TRAF6) and kinase 1 activated by transforming growth factor 1, which activates IkB kinase (IKK), leading to transcription of the NF-kB . Alquami et al.  corroborated these findings by demonstrating that rats fed with a high-fructose diet showed hepatic TRL4 overexpression.
The antifibrotic and hepatoprotective effects of TEL in different animal models  and human have been reported in several studies. TEL has been shown to have hepatoprotective effects on NAFLD decreasing hepatic fibrosis via its antioxidant and anti-inflammatory activity by preventing NF-kB signaling pathway stimulation . Similar results were described in humans were TEL reduced hepatic oxidative stress and fibrogenesis in patients with NAFLD and chronic hepatitis C .
Telmisartan reduced liver damage resulting from type I diabetes mellitus  and when associated with propranolol reduced the liver fibrosis signs in a murine model of primary sclerosing cholangitis (PSC) . Yi et al. showed that TEL was also able to prevent liver fibrosis in a rat bile duct ligation model . In mice fed with a high-fat diet treated with streptozotocin (STZ) low dose (2 days after birth), treatment with TEL reduced liver inflammation and fibrosis . Similarly, TEL reduced short- or long-term diet-induced hepatic fibrosis in rats  preventing hepatocellular carcinoma . The anti-inflammatory activity of TEL can be partly explained by the RAS blockade (AngII/AT1R), which plays an important role in the induction and maintenance of inflammation and oxidative stress [51,52,53].