Antiobesity Action of ACAM by Modulating the Dynamics of Cell Adhesion and Actin Polymerization in Adipocytes

Abstract

Coxsackie virus and adenovirus receptor-like membrane protein (CLMP) was identified as the tight junctionassociated transmembrane protein of epithelial cells with homophilic binding activities. CLMP is also recognized as adipocyte adhesion molecule (ACAM), and it is upregulated in mature adipocytes in rodents and humans with obesity. Here, we present that aP2 promoter-driven ACAM transgenic mice are protected from obesity and diabetes with the prominent reduction of adipose tissue mass and smaller size of adipocytes. ACAM is abundantly expressed on plasma membrane of mature adipocytes and associated with formation of phalloidin-positive polymerized form of cortical actin (F-actin). By electron microscopy, the structure of zonula adherens with an intercellular space of ∼10-20 nm was observed with strict parallelism of the adjoining cell membranes over distances of 1-20 mm, where ACAM and g-actin are abundantly expressed. The formation of zonula adherens may increase the mechanical strength, inhibit the adipocyte hypertrophy, and improve the insulin sensitivity.Quite a few adhesion molecules have been identified by molecular genetics as well as gene expression profile studies in adipocytes derived from experimental models and human studies. For instance, only cadherins were reported to be expressed in premature adipocytes. In the cell lines, such as C3H10T1/2 and 3T3-L1 cells, N-cadherin and cadherin-11 are expressed, and they are prominently suppressed by the induction of adipocyte differentiation and downregulated to very low levels after the full differentiation (1). Transgenic (Tg) expression of dominant-negative N-cadherin decreased bone formation, delayed acquisition of peak bone mass, and increased body fat (2). Although the information of adhesion molecules in adipocyte biology is limited, we identified adipocyte adhesion molecule (ACAM) from the visceral adipose tissues of OLETF (Otsuka Long-Evans Tokushima fatty) rats by PCR-based cDNA suppressive subtraction methods (3). Mouse ACAM was independently identified as adipocyte-specific protein 5 (ASP5) from 3T3-L1 cells by using signal sequence trap by a retrovirus-mediated expression screening method (4). Human ACAM had been identified as coxsackie virus and adenovirus receptor-like membrane protein (CLMP) by bioinformatics approaches, and Raschperger et al. (5) demonstrated that CLMP is a component of the tight junction of epithelial cells and colocalized with zonula occludens-1. ACAM/CLMP belongs to CTX (cortical thymocyte marker in Xenopus), and they are characterized by extracellular variable (V-type) and constant (C2-type) immunoglobulin domains, which are involved in the homophilic adhesion and aggregation of the cells. Although we reported the expression of ACAM increased in mature adipocytes in genetically obese db/db and diet-induced obesity mice, and also in adipose tissues

Cell-cell communication mediated by the CAR subgroup of immunoglobulin cell adhesion molecules in health and disease

“…These mice exhibited a significant reduction of body and fat pad weight as well as a significantly improved glucose tolerance and insulin sensitivity. In addition, adipocyte-specific expression of Clmp in transgenic CLMP mice under HFHS chow mediated a homotypic adhesion of adipocytes, formed zonula adherens structures and promoted actin polymerization (Murakami et al, 2016). Taken together, these findings indicate a role of CLMP in adipocyte function and obesity.…”

“…When obesity was stimulated in OLETF rats by administration of the hormone pioglitazone, the white adipose tissue of these animals upregulated Clmp transcript and CLMP protein as compared to non-treated OLETF rats, suggesting that CLMP might function in the conversion of premature to mature adipocytes (Eguchi et al, 2005). In a recent study Murakami and colleagues demonstrated that adipocyte-specific expression of CLMP in transgenic mice were protected from obesity under a highfat high-sucrose (HFHS) chow (Murakami et al, 2016). These mice exhibited a significant reduction of body and fat pad weight as well as a significantly improved glucose tolerance and insulin sensitivity.…”

“…In conclusion, since its discovery the knowledge about CLMP is gradually advancing and demonstrates multiple functions for CLMP in the organism. CLMP has been associated with obesity (Eguchi et al, 2005;Murakami et al, 2016;Van der Werf et al, 2012), the human intestinal disorder CSBS (Van der Werf et al, 2015 as well as with the peristalsis of the gastrointestinal and urogenital system (Langhorst et al, in preparation). The function of CLMP in the central nervous system where it is highly expressed remains to be determined.…”

Skin aging as a mechanical phenomenon: The main weak links

“…Thus, the adherence on the dermal-sWAT interface must, additionally to the adherence on the dermal-epidermal interface, influence the mechanical behavior of the composite skin/sWAT. While less is known about morphological structures involved in dermal-sWAT adherence, it can be strongly assumed that COL6 [ 78 ] and CLMP (Coxsackie virus and adenovirus receptor-like membrane protein) [ 79, 80 ] participate on this junction. It was stated that CLMP, also known for adipose tissue as adipocyte adhesion molecule (ACAM), is strongly involved in production of zonula adherence between the cells and significantly influences the integral mechanical strength of the tissue [ 79 ].…”

The IgCAM CLMP regulates expression of Connexin43 and Connexin45 in intestinal and ureteral smooth muscle contraction in mice

“…It has a widespread tissue and organ distribution in mice, with highest expression in the brain and heart based on northern blot data ( Raschperger et al, 2004 ; Eguchi et al, 2005 ). CLMP colocalizes with the tight-junction markers zonula occludens protein 1 (ZO-1) and occludin in transfected cells ( Raschperger et al, 2004 ; Eguchi et al, 2005 ; Murakami et al, 2016 ; Van Der Werf et al, 2012 ). CLMP induces homotypic aggregation when overexpressed in non-polarized Chinese hamster ovary (CHO) cells ( Raschperger et al, 2004 ), but its in vivo function is not well defined.…”