Telmisartan prevents diet-induced obesity and preserves leptin transport across the blood-brain barrier in high-fat diet-fed mice

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 gavage. In addition to broadly characterizing the metabolism of leptin, we determined leptin uptake into the brain by measuring BBB transport of radioactively labeled leptin after long-term and short-term TEL treatment. Additionally, we assessed BBB integrity in response to angiotensin II in vitro and in vivo. We found that HFD markedly increased body weight, energy intake, and leptin concentration but that this effect was abolished under TEL treatment. Furthermore, glucose control and, most importantly, leptin uptake across the BBB were impaired in mice on HFD, but, again, both were preserved under TEL treatment. BBB integrity was not impaired due to angiotensin II or blocking of angiotensin II receptors. However, TEL did not exhibit an acute effect on leptin uptake across the BBB. Our results confirm that TEL prevents DIO and show that TEL preserves leptin transport and thereby prevents leptin resistance. We conclude that the preservation of leptin sensitivity is, however, more a consequence than the cause of TEL preventing body weight gain.

Telmisartan prevents development of obesity and normalizes hypothalamic lipid droplets

“…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.…”

“…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.…”

“…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).…”

Effect of High-Fat Diets on Oxidative Stress, Cellular Inflammatory Response and Cognitive Function

“…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].…”

Modeling Diet‐Induced Metabolic Syndrome in Rodents

“…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...…”