Monocyte/macrophage cell lineage derived cells that are directly involved in osteoclastogenesis are known as osteoclasts. It is well characterized that different types of mediators such as NF-κB, RANKL, osteopontin (OPN), TNF-α, IL-6, M-CSF, and monocyte chemoattractant protein 1 (MCP1) have prominent roles to induce this process (Redlich and Smolen, 2012; Roy, 2013).

Osteocytes are fully mature osteoblasts that are abundantly (more than 90%) distributed throughout the mineralized bone matrix and bone surface (Bellido, 2007). Osteocytes form the lacunocanalicular network that acts as a mechanosensory system and is appropriate for mechanotransduction through which mechanical energy is transformed into biochemical signaling. Osteocyte apoptosis is very important to osteoclastogenesis because apoptotic osteocytes release immunostimulatory molecules that instruct nearby osteocytes and macrophages to produce VEGF, RANKL and other proinflamatory cytokines like TNF-α, IL-6, IL-1 (Jilka et al., 2013; Komori, 2013). Physical inactivity is a major cause of osteocyte apoptosis and it has been observed that individuals with long lasting bed rest and victims of paralysis have a greater chance of inducing osteocyte apoptosis (Bellido, 2007). Obesity is directly associated with physical immobilization (Pietilainen et al., 2008) and decreased synthesis of estrogen in the body (Freeman et al., 2010). Elevated GC levels and low-levels of estrogen are associated with higher prevalence of osteocyte apoptosis (Moutsatsou et al., 2012; Jilka et al., 2013). Reduced estrogen levels are also associated with increased production of TNF-α, that is inhibiting NO production and intracellular Ca²⁺ while strongly reducing F-actin content, resulting in decreased osteocyte stiffness followed by loss of bone mass (Osta et al., 2014). These additive effects increase osteocyte apoptosis within obese individuals.

Obesity induces adipocyte differentiation from mesenchymal stem cells. The differentiated lipid cells accumulate within the bone marrow, thereby expanding the area of marrow cavity. The expanded bone marrow cavity containing bone is more susceptible to fractures than bone without an expanded cavity. The expanded bone cavity also leads to decreased bone microcirculation (Cao, 2011). Type I collagen and minerals are two important structural components of the bone tissue and the bone strength primarily depends on the quantity of collagen and BMD. An in situ study by Chun et al. concluded that high-fat diets acutely trigger the MMP14-dependent degradation of type I collagen fibers (Chun et al., 2010). Other studies have demonstrated a differential impact of lipid on BMD with visceral adipose tissue (VAT) having potential detrimental effects on BMD (Bredella et al., 2011). High fat diet (HFD) has a pivotal role in bone formation because it markedly reduces the rate of Ca²⁺ absorption by the intestine and thereby decreases the availability of Ca²⁺ required for osteogenesis (Xiao et al., 2010; Cao, 2011). Decreased levels of vitamin D are a hallmark of osteoporosis and bone fractures (Roy, 2013). Vitamin D deficiency in the serum prevents intestinal uptake of Ca²⁺ from the diet and thereby signals the parathyroid gland to secret increased levels of PTH. Increased secretion of PTH induces osteolysis and prevents osteogenesis by supplying adequate levels of calcium and phosphorus in the blood necessary for metabolic processes and neuromuscular function (Stojanovic et al., 2011; Binkley, 2012). Although a normal level of PTH is beneficial to bone health, elevated secretion of PTH has been identified as a negative regulator of osteoblastogenesis (Zhang et al., 2011; Lampropoulos et al., 2012). During normal levels of PTH in the blood, it binds the PTH1R and induces the expression of BMP2 via PTH1R-cAMP-PKA-CREB signaling pathway (Zhang et al., 2011). In contrast, during hyper secretion of PTH, binding of PTH with PTH1R activates PKA and ERK and then, in turn, induction of the expression of MGP on the osteoblast, which is a potent inhibitor of BMP signaling (Lampropoulos et al., 2012; Roy, 2013). PTH binding also causes the internalization of the PTH1R-TGFβR complex that sequesters TGF-β signaling in osteoblastogenesis (Chen G. et al., 2012). Vitamin D is not only playing a role in calcium and phosphorus homeostasis in the blood, but it is also required for the activation of skeletal muscle as muscle contraction is a calcium dependent process (Stojanovic et al., 2011; Binkley, 2012; Girgis et al., 2013). Obesity is a possible risk factor for decreases in vitamin D related functions because vitamin D levels are significantly lower in obese subjects compared to lean subjects and this results in an increased risk of bone fracture and osteoporosis (Segula, 2014; Pereira et al., 2015).

Beyond the effect of HFD in bone formation, HFD is also responsible for increased body weight. This excess body weight may exert its pressure on the skeletal system as well as increase the risk of falling and thereby induce the risk of fractures of the weak bones (Townsend et al., 2008; Himes and Reynolds, 2012). Several researchers have come to the conclusion that although obesity may be helpful for bone health, obesity and DM induced neuropathy may trigger osteolysis (Sinacore et al., 2008).

Systemic oxidative stress has been identified as a potential risk factor of osteoporosis and bone fractures because increased ROS due to lipid oxidation sequesters the differentiation of preosteoblasts to osteoblasts through inhibiting Wnt signaling while inducing RANKL mediated osteoclast activation (Ng and Duque, 2010; Srinivasan et al., 2010). Oxidative stress also triggers the overexpression of PPAR-γ and thereby induces the differentiation of adipocytes, rather than osteoblasts, from MSC (Ng and Duque, 2010). One study conducted on a mouse model indicated that mice deficient in superoxide dismutase (SOD) have elevated oxidative stress and decreased muscle mass and strength compared to wild-type mice (Smietana et al., 2010). Numerous studies have come to the conclusion that obese individuals contain high-levels of ROS in their adipose tissue due to over nutrition and inflammation (Krawczyk et al., 2012).

The exact role of I/IGF-1 in skeletal muscle has been extensively examined, and it was discovered that I/IGF-1 is the major protein synthesis pathway in skeletal muscle (O'Neill et al., 2015; Sharples et al., 2015) In order to determine the effect of I/IGF signaling on skeletal muscle mass, O'Neill et al. generated mice with muscle-specific knockout of IGF-1R and the insulin receptor (IR). The IGF-1R/IR knockout mice showed greater than 60% decrease in muscle mass, confirming the vital role of I/IGF signaling on skeletal muscle mass (O'Neill et al., 2015). The role of IGF-1 signaling in muscle atrophy is mainly determined by the activity of AKT, which is an intermediate signaling molecule of the IGF-1 pathway. AKT induces activation of the mammalian target of rapamycin (mTOR), which then activates S6K1, ultimately stimulating protein synthesis (Hitachi and Tsuchida, 2014) (Figure 4). AKT prevents proteolysis by repressing the FOXO family of transcription factors, and induces protein synthesis through the mTOR signaling pathway. GSK3β is a potential inhibitor of protein synthesis due to its ability to inhibit Eukaryotic translation initiation factor 2B (eIf2B) and nebulin. AKT plays a major role in muscle growth by sequestering GSK3β, thus preventing GSK3β's inhibition of protein synthesis (Schiaffino et al., 2013). It is well documented that obesity, T2DM and metabolic syndrome are associated with the progression and development of IR (Martins et al., 2012; Ruiz-Alcaraz et al., 2013). Decreased mRNA levels of IRS-1, phosphoinositide 3-kinase (PI3K), GLUT-1, GLUT-4, GSK-3 isoforms and phosphoinositide-dependent kinase-1 (PDK1) were observed in an expression study conducted on muscle samples of obese women (Colomiere et al., 2010). Similarly, reduced activation of AKT, p70S6 kinase, and mTOR were found in the skeletal muscle of obese mice and Zucker rats (Akhmedov and Berdeaux, 2013). Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid phosphatase that acts against the action of PI3K by converting phosphatidylinositol (3,4,5)-trisphosphate (PIP₃) to PIP₂ and preventing AKT from docking on the plasma membrane (Schiaffino et al., 2013). It has been demonstrated in mice fed a high fat diet, that PIP₃ levels are reduced, while PTEN expression was increased (Akhmedov and Berdeaux, 2013). This observation supports the notion that obesity-induced increases in PTEN directly decrease muscle growth through the inhibition of AKT.

Myostatin is known as a negative regulator of myogenesis and is produced mainly by skeletal muscle, as shown by the finding that myostatin induces FOXO dependent upregulation of atrophy-related ubiquitin ligases like MuRF1 and atrogin 1 in cultured myocytes (Bonaldo and Sandri, 2013). Deactivation of the IGF-1-PI3K-AKT signaling pathway and upregulation of FOXO1 signaling is achieved by myostatin treatment (Rodriguez et al., 2014). Several studies have reported that binding of myostatin with its receptor, ActRIIB, activates SMAD 2/3 dependent signaling pathways in order to transcribe atrogenes (MacKenzie et al., 2013) (Figure 4). The proteins generated from these atrogenes inhibit the expression of MyoD and myogenin. Increased phosphorylation of SMAD2/3 proteins in obese individuals is associated with elevated levels of myostatin in skeletal muscle as well as an approximately two-fold decrease in MyoD and myogenin mRNA levels (Akhmedov and Berdeaux, 2013). Research conducted on extremely obese women determined the expression levels of myostatin within their myotubes had a 2.9-fold increase in the secretion of myostatin. From this data, it can be concluded that elevated levels of myostatin are associated with obesity (Hittel et al., 2009), and that this contributes to decreased muscle mass.

Leptin is a 167-amino acid peptide and is the product of the ob gene that is secreted by white adipose tissue (WAT) and also by a variety of other tissues including placenta, mammary gland, ovary, skeletal muscle, stomach, pituitary gland, and lymphoid tissue (Sainz et al., 2009; Park and Ahima, 2015). Binding of leptin with its receptor (Ob-R) activates cytoplasmic tyrosine kinases of the Janus kinase family (JAKs), which then activate STAT proteins (Ceddia, 2005) (Figure 4). It has been reported that muscle mass and fiber size are significantly lower in leptin deficient ob/ob mice compared to wild type mice that were administered leptin. This data indicates that decreased leptin is associated with reduced skeletal muscle mass in leptin-deficient ob/ob mice (Sainz et al., 2009). Leptin administration in 12 week old ob/ob mice show upregulation of myocyte proliferation, elevated myogenin and myonectin transcript levels in addition to reduced mRNA expression of myostatin, dystrophin, MuRF1 and MAFbx (Rodriguez et al., 2015). Recombinant leptin bearing mice show higher expression levels of MyoD and myogenin compared to leptin receptor knockout mice. Myoblast formation rates are also higher in these mice (Arounleut et al., 2013). Both leptin and insulin resistance in myocytes are associated with the onset of obesity, type 2 diabetes, and other metabolic disorders (Yang et al., 2012). Combined, these side effects of obesity dramatically impair muscle synthesis.

High doses or chronic administration of IL-6 in rats or mice cause increased degradation of proteins in skeletal muscle, although the normal levels of IL-6 have been proven hypertrophic (Munoz-Canoves et al., 2013; Pelosi et al., 2014). Insertion of the IL-6 gene into transgenic mice has been shown to elevate circulating IL-6, which is associated with severe muscle atrophy by the age of 10 weeks (Munoz-Canoves et al., 2013). Blockade of IL-6 signaling by the IL-6R antibody causes the regeneration of muscle (Carson and Baltgalvis, 2010). Indirect effects of IL-6 on IGF-1 signaling have also been reported. Increased circulating levels of IL-6 are associated with significantly reduced serum IGF-1 levels and elevated expression of SOCS3 mRNA in muscle (Munoz-Canoves et al., 2013; Pelosi et al., 2014), suggesting the role of IL-6 as a negative regulator of IGF-1 signaling. The entire mechanism by which IL-6 induces SOCS3 overexpression is still obscure, but evidence supports the hypothesis that IL-6 exerts its effect mainly through the JAK-STAT3 signaling pathway (Figure 4). In accordance with this finding, infusion of IL-6 in skeletal muscle induced STAT3 activation and overexpression of SOCS3 transcription, with a reduced number of myofibrillar proteins (Munoz-Canoves et al., 2013). Recently, the expression levels of IL-6 and its receptor, IL-6R, from lean, overweight and obese individuals were examined and it was determined that expression levels of IL-6 and IL-6R were elevated in obese individuals compared to the lean and overweight groups (Sindhu et al., 2015). A recent study showed that the overexpression of SOCS3 in skeletal muscle interferes with calcineurin signaling leading to defects in the sarcoplasmic reticulum and mitochondria. Obesity is associated with overexpression of SOCS3 in human and rodent skeletal muscle (Jorgensen et al., 2013). SOCS3 also exerts its negative effect on muscle by sequestering leptin, leading to the leptin resistance in skeletal muscle observed in obesity (Yang et al., 2012; Jorgensen et al., 2013).

It has been identified from several studies that elevated levels of TNF-α are associated with increased muscle atrophy and apoptosis (Gallo et al., 2015). Obesity and T2DM are associated with a chronic inflammatory response that is characterized by increased production of TNF-α and other proinflammatory cytokines (Steinberg et al., 2006). TNF-α exerts its effects through the NF-κB and P³⁸/MAPK mediated signaling pathway and stimulates the expression of iNOS, MuRF1 and MAFbx (Hall et al., 2011; Fanzani et al., 2012; Wang et al., 2014) (Figure 4). iNOS induces the production of nitric oxide (NO), which inhibits MyoD (an important myogenic transcription factor) via peroxynitrite (ONOO⁻) generation. iNOS also suppresses muscle protein synthesis through oxidative modification of JUN-D by inhibition of mTOR signaling and by increased phosphorylation of eILF2α and eukaryotic elongation factor 2 (eEF2) (Hall et al., 2011). MuRF1 and MAFbx trigger muscle protein degradation via UPS (Fanzani et al., 2012; Wang et al., 2014). TNF-α may also act as a potential inhibitor of IGF-1/AKT signaling by inhibiting the activation of IRS via JNK (Schiaffino et al., 2013). High fat diet induced obesity is associated with increased activation of JNK1 resulting in the development of obesity-induced insulin resistance (Sabio et al., 2010). Obesity is also associated with peripheral neuropathy mediated muscle atrophy or direct induction of muscle atrophy through TNF-α mediated pathways, thereby increasing muscle weakness (Sishi et al., 2011; Van et al., 2011).

A knockout study in mice has shown that endogenous IL-10 attenuates IL-6 expression in skeletal muscle (Huey et al., 2008). Inhibitory effects of IL-6 on insulin signaling in skeletal muscles are reduced dramatically following treatment with IL-10 (Kim et al., 2004), showing that IL-10 acts as a negative regulator of IL-6. Reduced levels of circulating IL-10 are observed in obese muscle causing lipid-induced insulin resistance. As a result, after 3 weeks of high fat diet, mice with muscle-specific overexpression of IL-10 develop obesity, but remain insulin sensitive in skeletal muscle (Hong et al., 2009; Makki et al., 2013). The insulin sensitizing and antidiabetic effects of adiponectin are well-characterized (Liu and Sweeney, 2014). Another study implied that disruption of muscle specific AdipoR1 downregulates the adiponectin-mediated elevation of intracellular Ca²⁺ concentration, and ultimately reduced the formation of oxidative type I myofibers in skeletal muscle through the inactivation of Ca²⁺/calmodulin-dependent protein kinase (CAMK), AMP dependent protein kinase (AMPK) and Sirtuin 1 (SIRT1) (Iwabu et al., 2010). In myocytes, binding of adiponectin with its receptor (ADIPOR1/2) activates AMPK signaling and enhances fatty acid oxidation and glucose uptake in muscle (Kwon and Pessin, 2013). Obesity is characterized by the decreased generation of adiponectin in skeletal muscle and thereby, may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetic models (Iwabu et al., 2010; Makki et al., 2013). The effects of omentin on muscle cells have not been identified yet, but several studies have reported its anti-inflammatory roles in other types of cells. For example, omentin-1 triggers AKT/PKB phosphorylation and thereafter accelerates insulin induced glucose uptake in human visceral and subcutaneous adipocytes. Additionally, omentin-1 inhibits C-reactive protein (CRP) and TNF-α induced NF-κB activation in human endothelial cells (Kwon and Pessin, 2013). Lower expression levels of omentin in the serum of obese individuals have been detected and are thought to be inversely related to obesity (Duan et al., 2011; Kwon and Pessin, 2013). IFNγ/NF-κB signaling pathway has been found to induce muscle atrophy in patients affected with cancer or chronic inflammation (Di et al., 2012). Elevated expression of IFN-γ and its receptor have been observed in obese subjects with defective muscle growth (Khan et al., 2014). All of these factors contribute to decreased muscle mass.

Obesity is characterized by ectopic lipid accumulation where elevated lipid storage takes place in subcutaneous and visceral adipose depots and non-adipose organs. There are two pools of lipids in skeletal muscles: extramyocellular lipids (EMCL) localized between muscle fibers and intramyocellular lipids (IMCL) located within muscle cells. An adipose tissue rich portion of EMCL which is closely associated with the muscle is known as intermuscular adipose tissue (IMAT). Accumulation of IMAT in obese individuals is positively correlated with insulin resistance and reduced muscle performance (Akhmedov and Berdeaux, 2013). Triacylglycerols (TAG), acyl CoAs, diacylglycerols and ceramides which are the major constituents of IMCL have been observed in higher levels in obese individuals compared to nonobese ones (Akhmedov and Berdeaux, 2013; Li et al., 2015). Lipotoxicity caused by accumulated acyl CoAs, diacylglycerols and ceramides adversely affect muscle development and regeneration (Akhmedov and Berdeaux, 2013). In obese rats and humans it was found that skeletal muscle triglycerides, diacylglycerols, and ceramides cause insulin resistance during obesity through different signaling mechanisms (Amati et al., 2011). Ceramides have also been recognized as a potential suppressor of myogenin, a transcription factor for myogenesis, as it suppresses the activity of myogenin through inhibition of phospholipase D (PLD) (Jadhav et al., 2013; Babenko and Kharchenko, 2015).

Obesity is associated with an elevated level of extracellular glucose in the body caused by IR and this glucose is a potential precursor of AGE formation (Unoki et al., 2010; Andrade et al., 2015). Binding of AGE with its receptor, RAGE, induces the formation of ROS via the NADPH mediated signaling pathway (Daffu et al., 2013) (Figure 4). AGE is also associated with apoptosis of smooth muscle cells through expression of Csp3 via p³⁸-MAPK dependent pathway (Wang et al., 2015). Overproduction of ROS causes the activation of FOXO3, a transcription factor that induces the expression of Bcl-2/adenovirus E1B 19kD-interacting protein 3 (Bnip3), which causes protein degradation, and also acts as an inhibitor of mTOR (Frost and Lang, 2011). Elevated levels of ROS may trigger muscle atrophy through three different signaling pathways: (1) the Ca²⁺ dependent calpain signaling pathway, (2) the MAPK-JNK/p³⁸/ERK1/2 signaling pathway, and (3) the NF-κB signaling pathway (Fanzani et al., 2012).

Several studies have reported the role of GCs in muscle atrophy. However, in 2013, Schakman et al. elucidated the effects of GCs on muscle atrophy by illustrating decreased fiber cross-sectional areas and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased muscle proteolysis through the activation of UPS and lysosomal systems. The effect of GC on these two proteolytic systems is mediated through the upregulation of several atrogenes like FOXO, Atrogin-1, and MuRF-1 (Bonaldo and Sandri, 2013; Schakman et al., 2013; Schiaffino et al., 2013; Patel et al., 2014). GCs exert their inhibitory effects on muscle protein synthesis mainly through inhibition of the mTOR/S6 kinase 1 pathway (Schakman et al., 2013; Patel et al., 2014). REDD1 and KLF15 are two potential inhibitors of mTOR and it has been concluded that GCs induce the expression of REDD1 and KLF15 genes in skeletal muscle during atrophy (Im et al., 2007; Shimizu et al., 2011). Overexpression of REDD1 and KLF15 in skeletal muscle has been implicated during obesity (Im et al., 2007; Williamson et al., 2014). Myostatin is a negative regulator of muscle because it inhibits muscle cell proliferation and protein synthesis. It has been reported that GC treatment increases the expression of myostatin in myocytes (Patel et al., 2014). GCs further decrease glucose utilization by up regulating PDK4 expression in skeletal muscle (Figure 4), by binding with the glucocorticoid response element (GRE) since PDK4 is a suppressor of glucose oxidation (Jeong et al., 2012). Overexpression of PDK4 mRNA has been found in cultured myotubes from obese and type 2 diabetic patients (McAinch et al., 2015). The use of steroid hormone treatments in the development of different types of metabolic disorders is well-established, and the chronic use of steroid hormones, such as glucocorticoids, may trigger the development of obesity accompanied with rapid muscle atrophy (Lee et al., 2014; Patel et al., 2014).

Ang II has been identified as antagonistic to insulin action because several lines of evidence have proven that Ang II inhibits insulin-induced tyrosine phosphorylation of IRS1, activation of AKT, and GLUT4 translocation to the plasma membrane. These actions can be reversed by pretreating myotubes with losartan (blocker of AT1 and AT2 receptor) or apocynin (a NADPH oxidase inhibitor) (Wei et al., 2006). Ang II treated C2C12 cells showed reduced expression of the genes involved in mitochondrial biogenesis and also Ang II functionality was inhibited by the blockade of the AT2 receptor (AT2R) (Mitsuishi et al., 2009). These results suggest an important role of Ang II in the inhibition of insulin signaling as well as downregulation of mitochondrial biogenesis in skeletal muscle through NADPH oxidase activation and ROS generation (Wei et al., 2006; Mitsuishi et al., 2009). Binding of Ang II with its receptor, ATR1, induces NADPH oxidase mediated generation of ROS, which in turn induces the upregulation of MuRF1 through the NF-κB signaling pathway as well as activation of Csp3, ultimately accelerating protein degradation. Ang II is also reported to induce the expression of Myostatin, GC, TNF-α and IL-6 in muscle and thereby induces muscle atrophy (Yoshida et al., 2013). In 2014, however, Oliveira et al. found that inhibition of AT1R with an AT1 receptor blocker prevented IR in rats with diet-induced obesity (Oliveira-Junior et al., 2014).

Use of GH has been identified to improve physical fitness through accelerating collagen synthesis in the tendon and skeletal muscle that leads to better performance in exercise and increased muscle strength (Tavares et al., 2013). Obesity is associated with reduced levels of GH in the muscle and liver (Clasen et al., 2014). Deficiency of GH causes the reduction of muscle mass and strength and these can be reversed successfully by the supplementation of GH (Weber, 2002). GH triggers the higher expression of IGF-1 primarily of hepatic origin, although it also induces synthesis of IGF-1 in most non-hepatic tissues. A recent study showed that GH triggers STAT5b phosphorylation in muscle and fat in obese subjects along with increased expression of CISH and SOCS2, two potential cytokine inhibitors (Velloso, 2008).

Testosterone and estrogen have been characterized as positive regulators of skeletal muscle mass in adult males and females respectively (Enns and Tiidus, 2010; Kovacheva et al., 2010). Testosterone exerts its effects by suppressing oxidative stress and myostatin levels, and activation of JNK and the cyclin-dependent kinase inhibitor p21 (Enns and Tiidus, 2010). During obesity, both testosterone and estrogen hormone levels decrease significantly in older males and females, respectively (Freeman et al., 2010; Wang et al., 2011). It is well-established that reduced levels of vitamin D are frequently associated with inferior physical performance and increased risk of falls due to impaired muscle activities. Depletion of vitamin D levels is a hallmark of obesity-induced muscle atrophy (Cipriani et al., 2014).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.