Telmisartan prevents high-fat diet-induced neurovascular impairments and reduces anxiety-like behavior

Abstract

Angiotensin II receptor blockers (telmisartan) prevent rodents from diet-induced obesity and improve their metabolic status. Hyperglycemia and obesity are associated with reduced cerebral blood flow and neurovascular uncoupling which may lead to behavioral deficits. We wanted to know whether a treatment with telmisartan prevents these changes in obesity. We put young mice on high-fat diet and simultaneously treated them with telmisartan. At the end of treatment, we performed laser speckle imaging and magnetic resonance imaging to assess the effect on neurovascular coupling and cerebral blood flow. Different behavioral tests were used to investigate cognitive function. Mice developed diet-induced obesity and after 16, not 8 weeks of high-fat diet, however, the response to whisker pad stimulation was about 30% lower in obese compared to lean mice. Simultaneous telmisartan treatment increased the response again by 10% compared to obese mice. Moreover, telmisartan treatment normalized high-fat diet-induced reduction of cerebral blood flow and prevented a diet-induced anxiety-like behavior. In addition to that, telmisartan affects cellular senescence and string vessel formation in obesity. We conclude, that telmisartan protects against neurovascular unit impairments in a diet-induced obesity setting and may play a role in preventing obesity related cognitive deficits in Alzheimer’s disease.

Cognitive impairment and metabolite profile alterations in the hippocampus and cortex of male and female mice exposed to a fat and sugar-rich diet are normalized by diet reversal

“…On the other hand, object recognition tasks still depicted impaired memory performance in the HFHSD-fed mice. By analyzing free open-field exploration, we further found HFHSD-induced impairments in novel environment exploration and increased anxiety-like behavior (Prut & Belzung, 2003), as was also reported for mice exposed to HFD (Huber et al, 2021), and in line with a proposed obesity associated depression (e.g. Vagena et al, 2019).…”

“…Therefore, one might speculate that increased NAAG levels together with an increased A2A receptor tone in astrocytes causes a dysfunctional regulation of astrocyte-mediated neurovascular coupling. In support of this, neurovascular dysfunction has been reported after 16, but not 8 weeks, of HFD feeding (Huber et al, 2021).…”

Cognitive Impairment and Metabolite Profile Alterations in the Hippocampus and Cortex of Male and Female Mice Exposed to a Fat and Sugar-Rich Diet are Normalized by Diet Reversal

“…On the other hand, object recognition tasks still depicted impaired memory performance in the HFHSD-fed mice. By analyzing free open-field exploration, we further found HFHSD-induced impairments in novel environment exploration and increased anxiety-like behavior [ 25 ], as was also reported for mice exposed to HFD [ 28 ], and in line with a proposed obesity associated depression [ 29 ].…”

The AT1 Receptor Blocker Telmisartan Reduces Intestinal Mucus Thickness in Obese Mice

“…Thus, AngII receptor (type 1) blockers (ARBs) such as telmisartan (TEL) and losartan (LOS) are well-established in the treatment of hypertension and heart failure, particularly with regard to their cardiometabolic benefits ( Michel et al, 2016 ). Beyond these beneficial actions, ARBs have been demonstrated to preventively and curatively lower obesity in rodents ( Muller-Fielitz et al, 2011 ; Miesel et al, 2012 ; Muller-Fielitz et al, 2012 ; Muller-Fielitz et al, 2014 ; Muller-Fielitz et al, 2015 ; Schuchard et al, 2015 ; Schuster et al, 2018 ; Winkler et al, 2018 ; Gustaityte et al, 2019 ; Rawish et al, 2020 ; Huber et al, 2021 ) and humans ( Kintscher et al, 2007 ). The anti-obese potency of ARBs occurs mainly after high dosages and is independent of their ability to reduce blood pressure ( Muller-Fielitz et al, 2011 ; Muller-Fielitz et al, 2014 ).…”

“…ARB-induced weight loss correlates with a reduction of energy intake, fat mass, and size of adipocytes ( Miesel et al, 2012 ; Muller-Fielitz et al, 2012 ). Although the underlying mechanism remains a matter of debate, it was found that leptin-related ( Muller-Fielitz et al, 2011 ; Muller-Fielitz et al, 2012 ; Schuster et al, 2018 ) and other brain-related mechanisms ( Winkler et al, 2016 ; Rawish et al, 2020 ; Huber et al, 2021 ) are involved in ARB-induced regulation of energy homeostasis. Addressing brain-related mechanisms, we have repeatedly shown that obesity-induced leptin resistance is normalized by TEL, as leptin can once again cross the blood‒brain barrier ( Muller-Fielitz et al, 2011 ; Muller-Fielitz et al, 2012 ; Schuster et al, 2018 ).…”