Obesity induces neuroinflammation mediated by altered expression of the renin–angiotensin system in mouse forebrain nuclei

Abstract

Obesity is a widespread health concern that is associated with an increased prevalence of hypertension and cardiovascular disease. Both obesity and hypertension have independently been associated with increased levels of inflammatory cytokines and immune cells within specific brain regions, as well as increased activity of the renin-angiotensin system (RAS). To test the hypothesis that high-fat diet (HFD) induced obesity leads to an angiotensin-II (Ang-II)-dependent increase in inflammatory cells within specific forebrain regions that are important for cardiovascular regulation, we first assessed microglial activation, astrocyte activation, inflammation and RAS component gene expression within selected metabolic and cardiovascular control centers of the forebrain in adult male C57BL/6 mice given either a HFD or a low-fat diet (LFD) for 8 weeks. Subsequently, we assessed the necessity of the paraventricular nucleus of the hypothalamus (PVN) angiotensin type-1a (AT1a) receptor for these responses by using the Cre/lox system in mice to selectively delete the AT1a receptor from the PVN. These studies reveal that in addition to the arcuate nucleus of the hypothalamus (ARC), the PVN and the subfornical organ (SFO), two brain regions that are known to regulate blood pressure and energy balance, also initiate proinflammatory responses after the consumption of a diet high in fat. They further indicate that some, but not all, of these responses are reversed upon deletion of AT1a specifically within the PVN.

Leptin Mediates High-Fat Diet Sensitization of Angiotensin II–Elicited Hypertension by Upregulating the Brain Renin–Angiotensin System and Inflammation

“…The increased gene expression for RAS components and PICs were accompanied by increased microglial activation in the hypothalamus including the ARC, SFO and PVN. 32,34,35 Conversely, TNF-α upregulates LEPR-b protein level and cell surface expression, which can lead to an increased cellular response to leptin and soluble LEPR production in cultured cells. 15 These results suggest that in both the periphery and CNS, PICs also mediate the cardiovascular and metabolic effects of leptin.…”

Central Renin–Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II–Elicited Hypertension

“…29 TNF-α levels are increased in obesity and serve as a marker for obesity. 30 Recent studies have revealed that HFD feeding increases hypothalamic PIC expression including IL-1β, IL-6 and TNF-α, and several components of the RAS such as AT1-R. 14,31 The increased gene expression for the RAS and for PICs is accompanied by increased microglial activation in the hypothalamus including the arcuate nucleus (ARC), SFO and PVN. 13,32,33 Some of these responses were reversed upon deletion of AT1a specially within the PVN.…”

“…TNF-α) in both brain and peripheral tissues. 11,14,31,34 However, one recent study showed that in rats predisposed to DIO, the expression of proinflammatory biomarkers was increased in the mediobasal hypothalamus within 24 h of HFD onset, 13 suggesting that hypothalamic inflammation occurs prior to obesity onset. This raises questions as to what factor(s) or through which pathway HFD activates the CNS RAS and inflammation so that the brain is sensitized to circulating hypertensive agents in the initial stages of overnutrition before the advent of increased systemic inflammation and RAS activation.…”

The potential crosstalk between the brain and adipose tissue in Obesity

“…Annette et al (de Kloet et al, 2014) reported the evidence that HFD induced obesity leads to angiotensin II (Ang-II) dependent increase in the inflammatory cells within specific fore brain regions related to cardiovascular regulation in adult male rats. They found that HFD consumption stimulated PVN and subfornical organ (SFO) of the hypothalamus which are related to energy balance similar to the arcuate nucleus, these centers initiates pro-inflammatory response that increase the expression of angiotensin type-Ia receptors (AT-Ia) which are necessary for energy balance.These receptors (AT-Ia) of SFO are impacted and regulated by levels of circulating factors that are regulated by adipocytes, for example, leptin increases SFO AT-Ia receptors expression (Hilzendeger et al, 2012).…”

“…The PVN is found to be activated after high fat diet (de Kloet et al, 2014) and this resulted in activation of other pathways that intersect at the PVN leading to obesity related cardiovascular disease and inflammatory disease (Hill, 2012).…”