Function of astrocyte MyD88 in high-fat-diet-induced hypothalamic inflammation

Abstract

Background: A growing body of evidence shows that hypothalamic inflammation is an important factor in the initiation of obesity. In particular, reactive gliosis accompanied by inflammatory responses in the hypothalamus are pivotal cellular events that elicit metabolic abnormalities. In this study, we examined whether MyD88 signaling in hypothalamic astrocytes controls reactive gliosis and inflammatory responses, thereby contributing to the pathogenesis of obesity. Methods:To analyze the role of astrocyte MyD88 in obesity pathogenesis, we used astrocyte-specific Myd88 knockout (KO) mice fed a high-fat diet (HFD) for 16 weeks or injected with saturated free fatty acids. Astrocyte-specific gene expression in the hypothalamus was determined using real-time PCR with mRNA purified by the Ribo-Tag system. Immunohistochemistry was used to detect the expression of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, phosphorylated signal transducer and activator of transcription 3, and α-melanocyte-stimulating hormone in the hypothalamus. Animals' energy expenditure was measured using an indirect calorimetry system. Results:The astrocyte-specific Myd88 KO mice displayed ameliorated hypothalamic reactive gliosis and inflammation induced by injections of saturated free fatty acids and a long-term HFD. Accordingly, the KO mice were resistant to long-term HFD-induced obesity and showed an improvement in HFD-induced leptin resistance.Conclusions: These results suggest that MyD88 in hypothalamic astrocytes is a critical molecular unit for obesity pathogenesis that acts by mediating HFD signals for reactive gliosis and inflammation.

Deficiency of Tristetraprolin Triggers Hyperthermia through Enhancing Hypothalamic Inflammation

“…Hypothalamic microgliosis linked to elevated circulating levels of fatty acid affects the operation of hypothalamic neurons controlling appetite and energy expenditure such as agouti-related peptide (Agrp) and proopiomelanocortin (Pomc)-positive neurons [ 22 , 23 , 24 ]. Therefore, we evaluated the neuronal activity in the hypothalamic Arc, where Agrp and Pomc neurons are predominantly present, and hypothalamic Pvn, one of the major target nuclei of melanocortin signals derived from Pomc neurons, to determine whether the melanocortin pathway is involved in the induction of microglial activation caused by TTP downregulation.…”

“…After several washes with PB buffer, the sections were preincubated with 0.3 % Triton X-100 (Sigma-Aldrich) for 30 min at room temperature. The sections were then incubated with primary antibodies against rabbit TTP (1:500, abcam, Cambridge, UK) [ 36 ], rabbit Iba-1 (1:1000 dilution, Wako, Osaka, Japan) [ 24 ], rabbit c-fos (1:1000 dilution, Santa Cruz Biotechnology, Dallas, TX, USA) [ 37 ], and sheep alpha-MSH (1:1000 dilution, Millipore, MA, USA) [ 24 ] overnight at room temperature. Immunofluorescence was performed with a secondary antibody (Alexa Fluor 488-labeled anti-rabbit antibody; 1:1000 dilution; Invitrogen Life Technologies, Carlsbad, CA, USA) for 2 h at room temperature.…”

Toll-like Receptors in Viral Encephalitis

“…In neurons, TLR signaling has been shown to be implicated in intrinsic regulation of neuronal functions such as morphology, morphogenesis and excitability. Since, during viral encephalitis, neurons often are the primary target of pathogens, more studies are needed to delineate the functional role of TLRs in the intrinsic neuronal biology during infection [ 149 , 151 ].…”

Adiponectin Controls Nutrient Availability in Hypothalamic Astrocytes

“…Since the Gfap-CreER T2 mice expressed Cre recombinase under the control of the tamoxifen inducible GFAP promoter, 8-weekold Gfap-CreER T2 : Rpl22 HA mice received daily intraperitoneal injections for 5 days of tamoxifen (100 mg/kg,T5648, Sigma-Aldrich, St. Louis, MO, USA) dissolved in corn oil (C8267, Sigma-Aldrich). RNA isolation with the Ribo-Tag system was performed as described by a previous reporters [29,30]. Briefly, the hypothalamus was harvested and homogenized before RNA extraction.…”