1.2.1 Brown and white adipose tissue
Two types of adipose tissue exist: the white adipose tissue (WAT) and the brown adipose tissue (BAT). Brown adipose tissue is mainly located in the interscapular region and persists
fat vacuoles than white adipose tissue, but a high number of mitochondria, establishing its function in thermoregulation (Hansen and Kristiansen, 2006; Tanaka et al., 1997). Important for non-shivering thermogenesis is the activity of uncoupling protein 1 (UCP1), a proton pump located in the inner mitochondrial membrane, that uses the electrochemical gradient to cause the production of heat instead of ATP (Argyropoulos and Harper, 2002).
White adipose tissue is developing after birth and acts with its large fat vacuoles as a postprandial storage for triglycerides (Tanaka et al., 1997). White adipose tissue is composed of mature adipocytes that represent about 50% of the cells, preadipocytes, fibroblasts, macrophages and endothelial cells (Trayhurn, 2007). In addition to its function in lipid storage, adipose tissue acts as an endocrine organ regulating energy metabolism and homeostasis by producing factors like the adipokines adiponectin and leptin (Confavreux et al., 2009; Harwood, 2011; Kadowaki and Yamauchi, 2005; Takeda and Karsenty, 2008).
1.2.2 Factors produced by adipose tissue: Adipokines
Adipokines are cytokines that are primarily produced and secreted by adipose tissue (Tilg and Moschen, 2006). They exert various functions, including an involvement in glucose and insulin metabolism, in immune functions (TNFα and IL-6), angiogenesis and regulation of blood pressure (Lefterova and Lazar, 2009). The function of the most important adipokines adiponectin, resistin, leptin, as well as the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 6 (IL-6) on glucose and insulin metabolism as well as on mesenchymal cell differentiation are described in the following.
Adiponectin is the most abundant factor produced by adipocytes in the circulation whereby its level is inversely proportional to adipose tissue mass in the body (Reid, 2010). It was shown that adiponectin enhances insulin sensitivity and increases glucose uptake and fatty acid oxidation of adipose tissue and muscle. In addition, hepatic gluconeogenesis is inhibited by adiponectin (Galic et al., 2010). The functions on the metabolism were described to be exerted via the activation of AMP-activated protein kinase, an enzyme regulating glucose metabolism (Yamauchi et al., 2002a).
In contrast, resistin confers resistance to insulin. Resistin levels are increased in obesity that leads to the proposed role for resistin in the insulin resistance linked to obesity and type 2 diabetes (Steppan et al., 2001).
Leptin is the most studied adipokine that links bone and fat metabolism. Its level is directly proportional to the amount of adipose tissue in the body and leptin was shown to directly
influence insulin resistance (Levi et al., 2011). Leptin produced by adipocytes within the bone marrow exerts a direct effect on mesenchymal stromal cells and bone cells by stimulating osteoblast differentiation and inhibiting bone resorption (Hamrick and Ferrari, 2008). In vitro studies using human MSCs showed that leptin can also inhibit osteoclast differentiation via the regulation of OPG and RANKL (Hamrick and Ferrari, 2008; Holloway et al., 2002) and, in addition, can suppress adipogenic differentiation (Thomas et al., 1999). However, leptin can regulate bone and fat by a second indirect effect involving signaling via the hypothalamus. This role in central regulation of bone and adipose tissue mass is described in more detail in the following chapter.
Adipose tissue also produces the pro-inflammatory cytokines TNFα and IL-6 providing amongst others a possible link between systemic chronic inflammation and obesity-induced insulin resistance (Galic et al., 2010; Tilg and Moschen, 2006). Macrophages are the main producers of TNFα and IL-6 in adipose tissue and expression of these cytokines is increased in obesity (Galic et al., 2010; Rasouli and Kern, 2008; Waki and Tontonoz, 2007) due to an increased infiltration of macrophages into the adipose tissue (Galic et al., 2010). TNFα and IL-6 were described to inhibit insulin signaling, increase insulin resistance (Galic et al., 2010;
Rasouli and Kern, 2008; Waki and Tontonoz, 2007) and to enhance lipolysis (Green et al., 2004; Ji et al., 2011).
1.2.3 The co-regulation of adipose tissue and bone
A systemic connection between adipose tissue and bone based on leptin and osteocalcin became a central focus of research in metabolism in the last few years (Fig. 1.1). Leptin, a hormone produced by white adipocytes, acts via the hypothalamus to inhibit appetite and to increase energy expenditure. Leptin deficient ob/ob as well as leptin receptor deficient db/db mice were therefore described to develop obesity caused by hyperphagy (Bates et al., 2003;
Cohen et al., 2001; Coleman, 1978). Bone formation is inhibited by leptin independently of its influence on body weight through the sympathetic nervous system. This pathway is activating the β2 adrenergic receptors on osteoblasts (Takeda et al., 2002), thereby increasing ATF4-dependent the expression of Esp, a gene encoding for OST-PTP, a tyrosine phosphatase that reduces osteocalcin bioactivity by γ-carboxylation (Hinoi et al., 2008; Lee et al., 2007;
Yoshizawa et al., 2009). Consequently, leptin deficiency in mice leads to an increased bone formation (Ducy et al., 2000).
In turn, osteocalcin, an osteoblast specific protein, acts as a hormone that directly enhances pancreatic β-cell proliferation and insulin secretion and indirectly, via adiponectin increases insulin sensitivity and energy expenditure (Ferron et al., 2008; Lee et al., 2007), thereby regulating fat metabolism.
More recently, an important role for insulin signaling in osteoblasts was reported. Signaling via the insulin receptor, that is inhibited by Esp, first increases the expression of Runx2 promoting osteoblast proliferation and differentiation (Fulzele et al., 2010) and second, stimulates bone resorption due to a decreased expression of OPG. The resulting acidification in the resorption area is another mechanism leading to an increased amount of decarboxylated bioactive osteocalcin and therefore increases insulin production (Ferron et al., 2010a).
pancreas adipose tissue
brain
uncarboxylated
carboxylated
osteocalcin leptin bone
leptin leptin
insulin
Figure 1.1: Local and systemic interaction between adipose tissue and bone. Leptin, produced by adipocytes regulates fat metabolism and bone formation via the hypothalamus. In turn, osteocalcin, an osteoblast specific factor, acts on the pancreatic β-cells and the adipose tissue influencing fat metabolism. Also described in (Schett and David, 2010)