Visceral adipose tissue imparts peripheral macrophage influx into the hypothalamus

Abstract

Background Obesity is characterized by a systemic inflammation and hypothalamic neuroinflammation. Systemic inflammation is caused by macrophages that infiltrate obese adipose tissues. We previously demonstrated that high-fat diet (HFD)-fed male mice exhibited peripheral macrophage infiltration into the hypothalamus, in addition to activation of resident microglia. Since this infiltration contributes to neuroinflammation and neuronal impairment, herein we characterize the phenotype and origin of these hypothalamic macrophages in HFD mice. Methods C57BL/6J mice were fed HFD (60% kcal from fat) or control diet with matching sucrose levels, for 12–16 weeks. Males and females were analyzed separately to determine sex-specific responses to HFD. Differences in hypothalamic gene expression in HFD-fed male and female mice, compared to their lean controls, in two different areas of the hypothalamus, were determined using the NanoString neuroinflammation panel. Phenotypic changes in macrophages that infiltrated the hypothalamus in HFD-fed mice were determined by analyzing cell surface markers using flow cytometry and compared to changes in macrophages from the adipose tissue and peritoneal cavity. Adipose tissue transplantation was performed to determine the source of hypothalamic macrophages. Results We determined that hypothalamic gene expression profiles demonstrate sex-specific and region-specific diet-induced changes. Sex-specific changes included larger changes in males, while region-specific changes included larger changes in the area surrounding the median eminence. Several genes were identified that may provide partial protection to female mice. We also identified diet-induced changes in macrophage migration into the hypothalamus, adipose tissue, and peritoneal cavity, specifically in males. Further, we determined that hypothalamus-infiltrating macrophages express pro-inflammatory markers and markers of metabolically activated macrophages that were identical to markers of adipose tissue macrophages in HFD-fed mice. Employing adipose tissue transplant, we demonstrate that hypothalamic macrophages can originate from the visceral adipose tissue. Conclusion HFD-fed males experience higher neuroinflammation than females, likely because they accumulate more visceral fat, which provides a source of pro-inflammatory macrophages that migrate to other tissues, including the hypothalamus. Our findings may explain the male bias for neuroinflammation and the metabolic syndrome. Together, our results demonstrate a new connection between the adipose tissue and the hypothalamus in obesity that contributes to neuroinflammation and hypothalamic pathologies.

Bidirectional communication between brain and visceral white adipose tissue: Its potential impact on Alzheimer's disease

“… 63 The diet could induce the changes in macrophage migration to the hypothalamus, adipose tissue and peritoneal cavity, especially in men. 64 In addition, some hypothalamic macrophages were proved to originate from vWAT. 64 …”

“…Notably, the possible signaling pathways mediating the interaction between brain and vWAT are complex ( Figure 1 ). Specifically, we summarized the potential mechanisms or mediating factors mainly including autonomic nervous system, 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 neurotransmitters, 51 , 54 , 61 , 62 , 63 inflammation, 50 , 59 , 60 , 67 , 68 , 69 hormones, 52 , 54 , 65 , 66 fat metabolism 51 , 56 , 57 , 58 , 59 , 64 and glucose metabolism 53 , 54 , 57 on the basis of current studies.…”

Macrophage-Regulatory T Cell Interactions Promote Type 2 Immune Homeostasis Through Resistin-Like Molecule α

“…Peritoneal cavity cells (PECs) were recovered in a total of 5 mL of ice-cold PBS. Splenic macrophage isolation were performed according to previous studies (33).Visceral fat was dissected and single cell dissociation and staining performed as previously described (34). For flow cytometry, cells were blocked with 0.6 µg Rat IgG and 0.6 µg a-CD16/32 (2.4G2) 5 min, stained for 25 min with antibodies to CD11b (M1/70), MHCII (M5/114.15.2), CD11c (N418), CD4(RM4-5), Ly6C(HK 1.4), Ly6G(1A8), CD19(1D3) and CD8(53-6.7) (all from BioLegend, San Diego, CA); SiglecF (E50-2440) (BD Bioscience, San Jose, CA); F4/80 (BM8) (eBioscience, Santa Clara, CA).…”

The Properties and Functions of Glial Cell Types of the Hypothalamic Median Eminence

“…Being outside of the blood brain barrier (BBB) it is possible for other circulating immune cells to be found in the ME, as well as microglia. Indeed, the perivascular space of ME capillaries is populated with macrophages, and infiltration of the ME with macrophages in high-fat diet and obesity in mouse models may contribute to diet-induced hypothalamic inflammation (75)(76)(77). Pericytes may also able to dynamically respond to peripheral signals and regulate ME function.…”