Role of myeloid-derived macrophages in obesity-associated hypothalamic inflammation and leptin resistance

Abstract

High fat diet (HFD)-induced obesity (DIO) accompanies inflammatory responses in the adipose tissue, where myeloid-derived macrophage plays a central role. Recent study has demonstrated that microglia, the resident macrophage in the central nervous system, are activated in the hypothalamus of mice with DIO. However, the contribution of myeloid-derived macrophage in obesity-associated hypothalamic inflammation remains unclear. During my PhD course, I investigated the role of macrophage in the development of hypothalamic inflammation and metabolic complications in DIO mice. In lean mice, macrophage was found in the median eminence, hypothalamic perivascular space and meninges surrounding the hypothalamus. HFD significantly induced activation and infiltration of macrophage in the parenchyma of hypothalamic arcuate nucleus (ARC). Most hypothalamic macrophages express the microglial marker Iba1, indicating that they may differentiate to microglia. Parabiosis experiment failed to demonstrate recruitment of monocytes to the hypothalamus in both lean and DIO mice. Ki67 immunohistochemistry revealed increased local proliferation of the perivascular and meningeal macrophage in DIO mice. Inducible nitric oxide synthase (iNOS) expression was increased in the mediobasal hypothalamus and hypothalamic macrophage of DIO mice. Blockade of hypothalamic NOS significantly inhibited hypothalamic macrophage activation but no effect on resident microglia. Furthermore, hypothalamic NOS inhibition in DIO mice ameliorated leptin resistance and reduced enhanced proinflammatory cytokine expression. In summary, myeloid ？derived macrophage is activated in the hypothalamic ARC of obese mice and causes hypothalamic inflammation and leptin resistance via iNOS-dependent mechanisms.