Abstract:Obesity is a global health problem and treatment options are still insufficient. When chronically treated with the angiotensin II receptor blocker telmisartan (TEL), rodents do not develop diet-induced obesity (DIO). However, the underlying mechanism for this is still unclear. Here we investigated whether TEL prevents leptin resistance by enhancing leptin uptake across the blood-brain barrier (BBB). To address this question, we fed C57BL/6 mice a high-fat diet (HFD) and treated them daily with TEL by oral gava… Show more
“…Once a day, mice received TEL (8 mg/kg bw ) or vehicle by oral gavage in a volume of 5 µL/g body weight. TEL dosages were evaluated recently (Muller-Fielitz et al 2012) and have been confirmed in numerous studies both in rats (Miesel et al 2012, Muller-Fielitz et al 2014, Schuchard et al 2015, Winkler et al 2016, Gustaityte et al 2018 and in mice (Schuster et al 2018, Dapper et al 2019 to reveal antiobese effects. For administration, TEL was suspended in 10% gum arabic (Carl Roth GmbH, Karlsruhe, Germany), resulting in a suspension of 1.6 mg/mL TEL.…”
Section: Study Protocol (Part 1)mentioning
confidence: 95%
“…Weight loss was observed both when telmisartan (TEL) was administered daily via the oral route to rats with fully diet-induced obesity in a treatment setting (Muller-Fielitz et al 2014) and in patients during irbesartan therapy (Kintscher et al 2007). These antiobese effects were only observed after giving high dosages of the drug and were found to be class effects and independent both of blood pressure reduction and of peroxisome proliferator-activated receptor gamma (PPARγ) activation (Muller-Fielitz et al 2011, Schuster et al 2018.…”
Section: Introductionmentioning
confidence: 99%
“…However, human obesity is not associated with an absence of leptin but rather with resistance to leptin activity (Konner & Bruning 2012). We recently showed that (a) homozygous Zucker rats (which represent a genetic animal model for leptin resistance due to a onepoint mutation causing an amino acid substitution in the extracellular domain of the leptin receptor) remain obese despite ARB treatment, whereas heterozygous controls lose weight (Muller-Fielitz et al 2011), (b) TEL treatment restores leptin sensitivity (Muller-Fielitz et al 2015), and (c) TEL prevents diet-induced obesity and preserves leptin transport across the blood-brain barrier (BBB) in mice fed a high-fat diet (HFD) (Schuster et al 2018). In addition to preventing obesity and restoring leptin sensitivity, TEL treatment normalized plasma levels of triglycerides (TGs), while TGs were markedly enhanced in control rats, which became obese and leptin resistant as a result of HFD feeding (Muller-Fielitz et al 2014).…”
The AT1 receptor blocker telmisartan (TEL) prevents diet-induced obesity. Hypothalamic lipid metabolism is functionally important for energy homeostasis, as a surplus of lipids induces an inflammatory response in the hypothalamus, thus promoting the development of central leptin resistance. However, it is unclear as to whether TEL treatment affects the lipid status in the hypothalamus. C57BL/6N mice were fed with chow (CONchow) or high-fat diet (CONHFD). HFD-fed mice were gavaged with TEL (8 mg/kg/day, 12 weeks, TELHFD). Mice were phenotyped regarding weight gain, energy homeostasis, and glucose control. Hypothalamic lipid droplets were analyzed by fluorescence microscopy. Lipidomics were assessed by performing liquid chromatography-mass spectrometry in plasma and hypothalami. Adipokines were investigated using immunosorbent assays. Glial fibrillary acidic protein (GFAP) was determined by Western blotting and immunohistochemical imaging. We found that body weight, energy homeostasis, and glucose control of TEL-treated mice remained normal while CONHFD became obese. Hypothalamic ceramide and triglyceride levels as well as alkyne oleate distribution were normalized in TELHFD. The lipid droplet signal in the tanycyte layer was higher in CONHFD than in CONchow and returned to normal under TELHFD conditions. High hypothalamic levels of GFAP protein indicate astrogliosis of CONHFD mice while normalized GFAP, TNFα, and IL1α levels of TELHFD mice suggest that TEL prevents hypothalamic inflammation. In conclusion, TEL has anti-obese efficacy and prevented lipid accumulation and lipotoxicity, which is accompanied by an anti-inflammatory effect in the murine hypothalamus. Our findings support the notion that a brain-related mechanism is involved in TEL-induced weight loss.
“…Once a day, mice received TEL (8 mg/kg bw ) or vehicle by oral gavage in a volume of 5 µL/g body weight. TEL dosages were evaluated recently (Muller-Fielitz et al 2012) and have been confirmed in numerous studies both in rats (Miesel et al 2012, Muller-Fielitz et al 2014, Schuchard et al 2015, Winkler et al 2016, Gustaityte et al 2018 and in mice (Schuster et al 2018, Dapper et al 2019 to reveal antiobese effects. For administration, TEL was suspended in 10% gum arabic (Carl Roth GmbH, Karlsruhe, Germany), resulting in a suspension of 1.6 mg/mL TEL.…”
Section: Study Protocol (Part 1)mentioning
confidence: 95%
“…Weight loss was observed both when telmisartan (TEL) was administered daily via the oral route to rats with fully diet-induced obesity in a treatment setting (Muller-Fielitz et al 2014) and in patients during irbesartan therapy (Kintscher et al 2007). These antiobese effects were only observed after giving high dosages of the drug and were found to be class effects and independent both of blood pressure reduction and of peroxisome proliferator-activated receptor gamma (PPARγ) activation (Muller-Fielitz et al 2011, Schuster et al 2018.…”
Section: Introductionmentioning
confidence: 99%
“…However, human obesity is not associated with an absence of leptin but rather with resistance to leptin activity (Konner & Bruning 2012). We recently showed that (a) homozygous Zucker rats (which represent a genetic animal model for leptin resistance due to a onepoint mutation causing an amino acid substitution in the extracellular domain of the leptin receptor) remain obese despite ARB treatment, whereas heterozygous controls lose weight (Muller-Fielitz et al 2011), (b) TEL treatment restores leptin sensitivity (Muller-Fielitz et al 2015), and (c) TEL prevents diet-induced obesity and preserves leptin transport across the blood-brain barrier (BBB) in mice fed a high-fat diet (HFD) (Schuster et al 2018). In addition to preventing obesity and restoring leptin sensitivity, TEL treatment normalized plasma levels of triglycerides (TGs), while TGs were markedly enhanced in control rats, which became obese and leptin resistant as a result of HFD feeding (Muller-Fielitz et al 2014).…”
The AT1 receptor blocker telmisartan (TEL) prevents diet-induced obesity. Hypothalamic lipid metabolism is functionally important for energy homeostasis, as a surplus of lipids induces an inflammatory response in the hypothalamus, thus promoting the development of central leptin resistance. However, it is unclear as to whether TEL treatment affects the lipid status in the hypothalamus. C57BL/6N mice were fed with chow (CONchow) or high-fat diet (CONHFD). HFD-fed mice were gavaged with TEL (8 mg/kg/day, 12 weeks, TELHFD). Mice were phenotyped regarding weight gain, energy homeostasis, and glucose control. Hypothalamic lipid droplets were analyzed by fluorescence microscopy. Lipidomics were assessed by performing liquid chromatography-mass spectrometry in plasma and hypothalami. Adipokines were investigated using immunosorbent assays. Glial fibrillary acidic protein (GFAP) was determined by Western blotting and immunohistochemical imaging. We found that body weight, energy homeostasis, and glucose control of TEL-treated mice remained normal while CONHFD became obese. Hypothalamic ceramide and triglyceride levels as well as alkyne oleate distribution were normalized in TELHFD. The lipid droplet signal in the tanycyte layer was higher in CONHFD than in CONchow and returned to normal under TELHFD conditions. High hypothalamic levels of GFAP protein indicate astrogliosis of CONHFD mice while normalized GFAP, TNFα, and IL1α levels of TELHFD mice suggest that TEL prevents hypothalamic inflammation. In conclusion, TEL has anti-obese efficacy and prevented lipid accumulation and lipotoxicity, which is accompanied by an anti-inflammatory effect in the murine hypothalamus. Our findings support the notion that a brain-related mechanism is involved in TEL-induced weight loss.
“…Hippocampal injury is found in HFD-fed animals in response to increased blood-brain barrier permeability [71] due to circulating proinflammatory adipokines and reactive glial cytokine production [81]. Increased blood-brain barrier permeability that allows proinflammatory proteins into the hippocampus can initiate neuroinflammation and stimulate neurodegeneration [82].…”
Section: Mechanisms Responsible For High-fat Diet-induced Cognitivmentioning
Cognitive dysfunction is linked to chronic low-grade inflammatory stress that contributes to cell-mediated immunity in creating an oxidative environment. Food is a vitally important energy source; it affects brain function and provides direct energy. Several studies have indicated that high-fat consumption causes overproduction of circulating free fatty acids and systemic inflammation. Immune cells, free fatty acids, and circulating cytokines reach the hypothalamus and initiate local inflammation through processes such as microglial proliferation. Therefore, the role of high-fat diet (HFD) in promoting oxidative stress and neurodegeneration is worthy of further discussion. Of particular interest in this article, we highlight the associations and molecular mechanisms of HFD in the modulation of inflammation and cognitive deficits. Taken together, a better understanding of the role of oxidative stress in cognitive impairment following HFD consumption would provide a useful approach for the prevention of cognitive dysfunction.
“…All data presented herein were obtained from refs. [44,54,55,70,72,74,75,78,88,95,96,98,102–111,116,119–121,124–130,132,134–137,140–144,147–156,158,159,161,163–171,173–176...…”
Section: Diet Composition and Exposure Timementioning
Standardized animal models represent one of the most valuable tools available to understand the mechanism underlying the metabolic syndrome (MetS) and to seek for new therapeutic strategies. However, there is considerable variability in the studies conducted with this essential purpose. This review presents an updated discussion of the most recent studies using diverse experimental conditions to induce MetS in rodents with unbalanced diets, discusses the key findings in metabolic outcomes, and critically evaluates what we have been learned from them and how to advance in the field. The study includes scientific reports sourced from the Web of Science and PubMed databases, published between January 2013 and June 2020, which used hypercaloric diets to induce metabolic disorders, and address the impact of the diet on metabolic parameters. The collected data are used as support to discuss variables such as sex, species, and age of the animals, the most favorable type of diet, and the ideal diet length to generate metabolic changes. The experimental characteristics propose herein improve the performance of a preclinical model that resembles the human MetS and will guide researchers to investigate new therapeutic alternatives with confidence and higher translational validity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.