Author(s): Woon-Ki Kim 1, Eun-Kyung Choi 1, Ok-Joo Sul 1, Yeon-Kyung Park 1, Eun-Sook Kim 2, Rina Yu 3, Jae-Hee Suh 4, Hye-Seon Choi 1,*
Introduction
The prevalence of metabolic syndrome increases with menopause. A loss of ovarian function is associated with increased fat, along with metabolic pathologies including insulin resistance (IR) and type 2 diabetes (T2D) [1]. The fact that increasing numbers of postmenopausal women expect longer life spans requires an understanding of the pathologies and molecular mechanisms of metabolic diseases associated with menopause. Ovariectomy (OVX) in rodent is considered to resemble human menopause. OVX results in increase of fat mass [2], [3] and chronic inflammation accompanied by IR [4], [5], [6], [7], implying a connection between metabolic complications observed in OVX and obesity. Chronic inflammation, which simultaneously occurs in obesity, contributes to IR and T2D [8]. Adipose tissue macrophage (ATM) which accumulates in adipose tissue (AT) with increasing body weight, is suggested as responsible for chronic inflammation, resulting in mediating IR [8]. This suggestion is supported by findings that increased ATM is associated with an aggravation of insulin sensitivity [9], whereas decreased ATM reduces IR caused by high fat diet (HFD)-induced obesity [10].
Tremendous heterogeneity is observed with ATM according to the local metabolic microenvironment. There are two populations of macrophages, the one of which expresses CD11c, an M1 macrophage marker, is suggested to be specifically recruited to AT upon HFD [11]. M1 ATM produces tumor necrosis factor-[alpha], interleukin (IL)-6, and monocyte chemoattractant protein-1 (MCP-1), which induce IR, suggesting a connection between CD11c and IR. M2 ATMs have a different expression pattern with high levels of CD163, arginase-1, or IL-10, which are mainly associated with tissue repair [12].
MCP-1 (CCL2) plays critical roles in the development of inflammation and the recruitment of immune cells to the site of inflammation. In HFD-induced obesity, MCP-1 is highly expressed in AT, and circulating concentration is elevated, whereas administration of thiazolidinedione decreases MCP-1 levels [13], [14]. During menopausal transition, circulating level of MCP-1 has increased significantly, suggesting a role of MCP-1 as an indicator of hormonal change [15]. Increased serum MCP-1 level in humans correlates with markers of metabolic disorder including obesity, IR, and T2D [16]. Indeed MCP-1 inhibits insulin-induced glucose uptake [17]. In addition, high glucose levels induce monocytes to produce MCP-1 [18]. These results suggest a critical role of MCP-1 in inflammation associated with metabolic dysfunction. On the contrary, Park et al shows no correlation between circulating level of MCP-1 and obesity or IR [19].
In this study, we investigated the role of MCP-1 in OVX-induced metabolic perturbation, which is associated with CD11c-expressing ATM via up-regulation of ROS.
Results
MCP-1 Deficiency Decreases Visceral Adiposity and Metabolic Perturbation Induced by OVX
In previous studies, we demonstrated that OVX increases serum MCP-1 level [20]. To investigate whether MCP-1 contributes to OVX-induced metabolic dysfunction, we analyzed MCP-1-knockout (KO) mice, compared with wild type (WT) mice. The body weight increase of MCP-1-KO mice after sham surgery was slightly lower than WT mice at 18...