Circulating HDL levels control hypothalamic astrogliosis via apoA-I

Abstract

Meta-inflammation of hypothalamic areas governing energy homeostasis has recently emerged as a process of potential pathophysiological relevance for the development of obesity and its metabolic sequelae. The current model suggests that diet-induced neuronal injury triggers microgliosis and astrocytosis, conditions which ultimately may induce functional impairment of hypothalamic circuits governing feeding behavior, systemic metabolism, and body weight. Epidemiological data indicate that low circulating HDL levels, besides conveying cardiovascular risk, also correlate strongly with obesity. We simulated that condition by using a genetic loss of function mouse model (apoA-I) with markedly reduced HDL levels to investigate whether HDL may directly modulate hypothalamic inflammation. Astrogliosis was significantly enhanced in the hypothalami of apoA-I compared with apoA-I mice and was associated with compromised mitochondrial function. apoA-I mice exhibited key components of metabolic disease, like increased fat mass, fasting glucose levels, hepatic triglyceride content, and hepatic glucose output compared with apoA-I controls. Administration of reconstituted HDL (CSL-111) normalized hypothalamic inflammation and mitochondrial function markers in apoA-I mice. Treatment of primary astrocytes with apoA-I resulted in enhanced mitochondrial activity, implying that circulating HDL levels are likely important for astrocyte function. HDL-based therapies may consequently avert reactive gliosis in hypothalamic astrocytes by improving mitochondrial bioenergetics and thereby offering potential treatment and prevention for obesity and metabolic disease.

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

“…The association of vascular-specific GFAP (GFAP co-localized with CD31) with CAA was visualized using immunofluorescence and normalized to total cortical CAA area (e, g) and total vascular GFAP area (f, g) in the cortex. hypothalamic astrogliosis [60]; however, we did not observe any significant genotype effects on GFAP expression in the hypothalamus in the current study (Additional file 1: Figure S6a and b).…”

The melanocortin pathway and control of appetite-progress and therapeutic implications

“…5). The increased concentration of cAMP induced by MC4R is thought to activate exchange protein directly activated by cAMP (EPAC), leading to ERK1/2-dependent phosphorylation of the transcription factor cAMP response element (CRE) binding protein (CREB), increased transcription of cFos and reduced phosphorylation and activity of AMPK (Glas et al 2016, Yang & Tao 2016. In this respect, intracerebroventricular delivery of the MC3R/MC4R synthetic agonists induces anorexia as well as activation of transcription by CREB and expression of cFos in the PVN (Thiele et al 1998, Benoit et al 2000, Harris et al 2001, Lee et al 2001, Sarkar et al 2002, Lu et al 2003, Rowland et al 2010.…”

“…With this respect, decreased circulating high-density lipoprotein (HDL), a risk factor for cardiovascular disease, correlates with obesity (Woudberg et al 2016). When loss of HDL is simulated in mice by knockout of Apolipoprotein A1 (apoA-I), there is hypothalamic astrogliosis paralleled by disrupted hypothalamic mitochondrial function as well as by increased hepatic triglyceride content and glucose output (Gotz et al 2018). These data indicate that, in obesity, dyslipidemia with increased circulating saturated fatty acids and loss of HDL promotes hypothalamic inflammation and altered mitochondrial function in the hypothalamus.…”

“Hypothalamic Microinflammation” Paradigm in Aging and Metabolic Diseases

“…Indeed, astrocytes contain various immune pathways and can induce proinflammatory signaling and cytokine production via activation of glycoprotein 130, NF-kB, MAPK, and Jak/Stat1 pathways (Gorina et al, 2011;Haroon et al, 2011). Recently, it was recognized that obesity and related metabolic disorders are associated with astrogliosis, which might affect astrocytic functions (Buckman et al, 2013;Gö tz et al, 2018;Horvath et al, 2010;Kwon et al, 2017;Thaler et al, 2012). Research also showed that hypothalamic astrocytes from aged animals were more inflammatory Dalvi et al, 2017;Tsaousidou et al, 2014;Zhang et al, 2008 Inflammation affects regulatory signaling of AgRP neurons, leading to changes in energy and glucose disorders.…”