*3.1.4 Role of adipokines and myokines*

Skeletal muscle compounds 40% of total body weight in healthy individuals. The muscle is the major site for the insulin-stimulated glucose uptake and lipid metabolism, so it is an important part of metabolism maintenance [81].

Adipose tissue possesses more than 600 potentially secretory proteins, which means that more adipokines and myokines are still in line for discovery and characterization [82].

Additionally in adipokines there is a cross talk between these and myokines, which are synthetized by the muscle. Nevertheless, both tissues can express the same cytokines creating a regulation process with a strong communication. The most characterized cytokines are chemerin, TNFa, MCP-1 and IL-6. It is demonstrated that WAT deposits exist in skeletal muscle and facilitate communication, also, these tissues usually are in close anatomical proximity.

#### **Figure 2.**

*Adipose tissue differentiation and hyperplasia and hypertrophy consequences.*

The knowledge of the most important characterized myokines is as follows: IL-6: this increases in favor of the exercises, but it is recognized that it has a controversial role in the inflammatory or anti-inflammatory pathway.

Il-15: it mediates a beneficial effect on physical activity.

Irisin: it stimulates the development of brown adipose tissue activating MPK and ERK molecular ways, and it is regulated by the age and gender. This molecule has also a controversial role, because it has been reported to increase obesity.

Myonectin: it has a homology worth the sequence of adiponectin and promotes fatty acid uptaking in mice [82, 84–86].

Principally, the major role of the adipomyokines is contributing to metabolism, angiogenesis, blood vessel regulation, adipogenesis, myogenesis, and immune response [82]. On the other hand, it is important to remark the impact that macrophages have in metabolism, since they induce a response in both tissues. For example, when circulating monocytes respond to chemoattractant molecules, they migrate into adipose and muscle tissue, and then develop a phenotype depending on environmental necessities (**Table 1**) [94].

Finally, there is another terminology newly adopted by the scientist called organokines, because it has been suggested that all proteins secreted in various tissues or organs (liver, adipose tissue, muscle, and bone) have an intimate relationship in the context of the communication and regulation for the maintaining of homeostasis and that they are involved in a network of paracrine and endocrine cross talk [84].

#### *3.1.5 Emerging role of microRNAs in obesity*

In the context of complex diseases, obesity is the prototype of immunometabolic disease; it is considered a major factor that triggers metabolic risk and the development of secondary chronic illness2 , insulin resistance (IR), and metabolic syndrome (MS). The susceptibility of a subject to develop obesity will depend on different factors such as the repertoire of individual variations in an ensemble of relevant genes, their history of exposure to environmental risk factors, and the interaction between the lifestyle and metabolism, which is also modulated by the gene regulators [95–97].

Meanwhile, obesity presents many subclinical manifestations, characterized by alterations in lipids and carbohydrate metabolism at different levels; most of these changes is due to a low-grade systemic chronic inflammation [98, 99] that favors the development of IR. Adipose tissue is the primary anatomical site where IR disease takes place; in early stage this tissue became inflamed.


**19**

*Adipose Tissue in Health and Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.90559*

contributes to the related disease outcomes.

ment of T2D and other related diseases.

and IR.

for functional proteins.

protein decay [109, 110].

development of diseases in vivo.

scarcity of a miR indicates its level of regulation.

Novel findings on the immune-regulatory processes and metabolic mechanisms may open new avenues in the treatment of the common complex diseases as well as inflammatory component; research on basic and clinical advances in immunometabolism has evolved rapidly during the past years, and the beginning of new tools for the detection and characterization of regulation of inflammation in metabolic diseases with comorbidity may play an imperative role; nevertheless, the precise

Interplay in the regulation of inflammation and metabolic risk factors are a complex cluster. The inflammatory condition associated with adipose tissue represents a triggering factor in the etiology of the obesity pathological mechanisms and mainly

In the early stages of obesity, in white adipose tissue, primed immune cells are recruited as adiposity increases, and these cells became resident cells (mainly macrophages) and secrete proinflammatory adipokines that promote further recruitment of circulating monocytes [100–103]. Later, they polarize toward M1 macrophages, favoring a subclinical chronic inflammatory state [102, 104–106] secondary to irregular increase and distribution of fat depots [107]. In IR, the expression of genes implicated in glucose and lipid absorption and metabolism in liver and adipose tissue is dysregulated, at the same time, insulin signaling pathway in peripheral tissues is also disturbed [108]; this IR scenario precedes the develop-

The identification of diverse molecular mechanisms related to energy metabolism has allowed the definition of strategies for searching genes implied in obesity

In the decade that precedes us, experimental reports show the existence of small noncoding RNAs, which are identified as microRNAs, (miRs) with the function of regulating cellular processes through modulating the expression of genes that code

The insulin signaling pathways may be regulated by microRNAs (miRNA) that modulate the stability and translation of messenger RNAs (mRNA) by a particular mechanism of binding seeding sequences located in target genes, resulting in

Once synthesized, some miRNA can be released into circulation via exosomes, vesicular bodies, lipoproteins, simple extrusion, or apoptotic bodies. Most researches in the field have assessed the presence of circulating miRNA in many body fluids, being related to their impaired expression in tissues under physiological and pathological conditions. Several studies have shown a correlation of particular circulating miRNA with the development of different pathologies, positioning them as valuable biomarkers in silent diseases such as obesity, IR, and MS [111, 112]. Although rapid progress is being made in research on miRs, there is little availability of experimental tools with scientific value and mechanisms that lead from the discoveries of miRs to the therapeutic application in diseases. Therefore, the current demand is to explore the expression and biological function of miRs in the

The main considerations that are known are that the process of its biogenesis is governed by regulatory checkpoints, based on the fact that the sequence of the primary transcript does not correspond linearly to mature miR. The abundance or

Under physiological conditions, it has been shown that miRs modulate gene expression; however pathological stress increases or decreases its function. Therefore, its function will be defined by the effect on the expression of the genes to which it is directed. Predictions indicate that 60% of target mRNA genes have

mechanisms mediating this relationship remains poorly understood.

#### **Table 1.** *Best characterized adipomyokines.*

#### *Adipose Tissue in Health and Disease DOI: http://dx.doi.org/10.5772/intechopen.90559*

*Obesity*

The knowledge of the most important characterized myokines is as follows: IL-6: this increases in favor of the exercises, but it is recognized that it has a

Irisin: it stimulates the development of brown adipose tissue activating MPK and ERK molecular ways, and it is regulated by the age and gender. This molecule has

Myonectin: it has a homology worth the sequence of adiponectin and promotes

Principally, the major role of the adipomyokines is contributing to metabolism,

Finally, there is another terminology newly adopted by the scientist called organokines, because it has been suggested that all proteins secreted in various tissues or organs (liver, adipose tissue, muscle, and bone) have an intimate relationship in the context of the communication and regulation for the maintaining of homeostasis and that they are involved in a network of paracrine and endocrine cross talk [84].

angiogenesis, blood vessel regulation, adipogenesis, myogenesis, and immune response [82]. On the other hand, it is important to remark the impact that macrophages have in metabolism, since they induce a response in both tissues. For example, when circulating monocytes respond to chemoattractant molecules, they migrate into adipose and muscle tissue, and then develop a phenotype depending

In the context of complex diseases, obesity is the prototype of immunometabolic disease; it is considered a major factor that triggers metabolic risk and the

syndrome (MS). The susceptibility of a subject to develop obesity will depend on different factors such as the repertoire of individual variations in an ensemble of relevant genes, their history of exposure to environmental risk factors, and the interaction between the lifestyle and metabolism, which is also modulated by the

Meanwhile, obesity presents many subclinical manifestations, characterized by alterations in lipids and carbohydrate metabolism at different levels; most of these changes is due to a low-grade systemic chronic inflammation [98, 99] that favors the development of IR. Adipose tissue is the primary anatomical site where IR disease

IL-6 [87] IL-8 [88] MCP-1 [89] Irisin [82] PAI-1 [90] PEDF [91] FGF21 [92] Fstl 1 [93]

, insulin resistance (IR), and metabolic

controversial role in the inflammatory or anti-inflammatory pathway.

also a controversial role, because it has been reported to increase obesity.

Il-15: it mediates a beneficial effect on physical activity.

fatty acid uptaking in mice [82, 84–86].

on environmental necessities (**Table 1**) [94].

*3.1.5 Emerging role of microRNAs in obesity*

development of secondary chronic illness2

takes place; in early stage this tissue became inflamed.

gene regulators [95–97].

**18**

**Table 1.**

*Best characterized adipomyokines.*

Novel findings on the immune-regulatory processes and metabolic mechanisms may open new avenues in the treatment of the common complex diseases as well as inflammatory component; research on basic and clinical advances in immunometabolism has evolved rapidly during the past years, and the beginning of new tools for the detection and characterization of regulation of inflammation in metabolic diseases with comorbidity may play an imperative role; nevertheless, the precise mechanisms mediating this relationship remains poorly understood.

Interplay in the regulation of inflammation and metabolic risk factors are a complex cluster. The inflammatory condition associated with adipose tissue represents a triggering factor in the etiology of the obesity pathological mechanisms and mainly contributes to the related disease outcomes.

In the early stages of obesity, in white adipose tissue, primed immune cells are recruited as adiposity increases, and these cells became resident cells (mainly macrophages) and secrete proinflammatory adipokines that promote further recruitment of circulating monocytes [100–103]. Later, they polarize toward M1 macrophages, favoring a subclinical chronic inflammatory state [102, 104–106] secondary to irregular increase and distribution of fat depots [107]. In IR, the expression of genes implicated in glucose and lipid absorption and metabolism in liver and adipose tissue is dysregulated, at the same time, insulin signaling pathway in peripheral tissues is also disturbed [108]; this IR scenario precedes the development of T2D and other related diseases.

The identification of diverse molecular mechanisms related to energy metabolism has allowed the definition of strategies for searching genes implied in obesity and IR.

In the decade that precedes us, experimental reports show the existence of small noncoding RNAs, which are identified as microRNAs, (miRs) with the function of regulating cellular processes through modulating the expression of genes that code for functional proteins.

The insulin signaling pathways may be regulated by microRNAs (miRNA) that modulate the stability and translation of messenger RNAs (mRNA) by a particular mechanism of binding seeding sequences located in target genes, resulting in protein decay [109, 110].

Once synthesized, some miRNA can be released into circulation via exosomes, vesicular bodies, lipoproteins, simple extrusion, or apoptotic bodies. Most researches in the field have assessed the presence of circulating miRNA in many body fluids, being related to their impaired expression in tissues under physiological and pathological conditions. Several studies have shown a correlation of particular circulating miRNA with the development of different pathologies, positioning them as valuable biomarkers in silent diseases such as obesity, IR, and MS [111, 112].

Although rapid progress is being made in research on miRs, there is little availability of experimental tools with scientific value and mechanisms that lead from the discoveries of miRs to the therapeutic application in diseases. Therefore, the current demand is to explore the expression and biological function of miRs in the development of diseases in vivo.

The main considerations that are known are that the process of its biogenesis is governed by regulatory checkpoints, based on the fact that the sequence of the primary transcript does not correspond linearly to mature miR. The abundance or scarcity of a miR indicates its level of regulation.

Under physiological conditions, it has been shown that miRs modulate gene expression; however pathological stress increases or decreases its function. Therefore, its function will be defined by the effect on the expression of the genes to which it is directed. Predictions indicate that 60% of target mRNA genes have

similar binding sequences in the 3′UTR region for single or multiple miRs. These miRs exert their silencing function through two different mechanisms: translation inhibition (initiation or elongation) and target mRNA degradation. In the target genes for miRs, it is observed that 3′UTR regions have binding sites for multiple miRs; this suggests cooperation and redundancy of the effect on gene expression between the different miRs.

Currently, there are 1917 human miRNAs listed in the miRNA database miRBase (http://www.mirbase.org), representing 1% of all genes in the human genome. These miRNAs are predicted to target aprox. 30% of the human gene pool.

From the extraction of plasma and blood serum miRs from human and mammalian animal samples, they have been proposed as diagnostic biomarkers in the diseases. The attributes that stand out are that the miRs extracted from the serum have stability, and the results in the quantification are reproducible and consistent among individuals of the same species.

The logical sequence in the integral investigation of miRs is firstly to identify the presence in a given sample. The experimental tools used to measure the expression profile of miRs have been by microarray analysis or deep sequencing, while the determination of the level of expression of individual miRs has been performed by RT-PCR, in situ hybridization or northern blot.

However, the investigations carried out can be categorized from two conceptual points, the determination of the level of expression in which the most used methodological tool is real-time PCR analysis and global expression assays. The former stand out for their specificity while confirming the latter, while the latter provide a broad view of the presence and regulation of miRs.

Properly identifying the functionality and level of expression of a specific miR is limited due to the high degree of sequence homology between some miRs and the size of the molecule; the parallel application of different molecular tools strengthens the identification or quantification process of the level of expression. However, an unfavorable factor is the combined regulation of multiple genes or small changes in gene regulation that are lost in biological noise.

Enhancing the work of performing research surrounding these novel gene regulators will advance our understanding of miRNAs and their specific functions and will augment the opportunities to safely follow them as therapeutic targets [113].

#### **3.2 IR in muscle and liver**

Conventionally, insulin acts directly on the WAT under the cascade of the IRS1 axis, PI3K, and AKT, for glucose absorption, with a possible positive feedback of the phosphorylation of Ser388 from IRS2, by cyclin-dependent kinase 4 (CDK4) [114], culminating with lipolysis regulation. However, as described in previous sections of the chapter, inflammatory processes and alternative activation of macrophages favor the pathogenic adiposity in which the action of insulin is not carried out correctly and therefore does not slow the lipolysis process.

Although the mechanism of signaling pathways that links pathogenic adiposity to insulin resistance in skeletal muscle and liver has not been well defined due to the difficulty of modeling in vitro systems that allow cell coordination as in a complex organism, the process of understanding molecular bases has lagged behind the direct action of insulin in an organ or cell. The best way to associate it is the chronic surplus of energy that favors the accumulation of ectopic lipids in the liver and skeletal muscle that trigger the activation of pathways that impair insulin signaling, causing the decrease in glucose absorption in muscle cells and of glycogenesis in liver [115]**.**

**21**

*Adipose Tissue in Health and Disease*

with hyperinsulinemia.

*3.2.1 Liver*

*DOI: http://dx.doi.org/10.5772/intechopen.90559*

fore regulating serum hyperglycemia.

activity [120].

hyperglycemia [127].

*3.2.2 Muscle*

In a physiological stage with food withdrawal, the main source of glucose in the bloodstream is the liver. On the other hand, after absorption of nutrients by the intestine, the production of hepatic glucose should be interrupted in coordination

The most assertive explanations of how insulin acts to promote glucose homeostasis by inhibiting both glycogenolysis and hepatic gluconeogenesis have focused on the canonical pathway of insulin interacting directly in the liver by activating the insulin receptor (InsR) and the substrate of insulin receptor (IRS) and the phosphoinositol 3-kinase signaling cascade (PI3K/Akt/mTOR pathway) by inhibiting transcription of the forkhead box class O-1FOXO1 factor and thus gene transcription and activation of gluconeogenic enzymes such as phosphoenolpyruvate

However, it has been observed that suppression of hepatic glucose production is not totally dependent on the Akt activation pathway, for which remote insulin actions that interact indirectly with the physiological process of hepatic glucose have been studied. On one hand, the reduction of PCK1 and glucose 6-phosphatase (G6Pase) through cerebral insulin action activates the ATP-sensitive potassium channels (KATP) of hypothalamus and stimulate the vagal transmission and STAT3 activation [118, 119], blocking the *de novo* glucose formation by the liver and there-

On the other hand, insulin action in WAT suppresses lipolysis and reduces the fatty acids flow into the liver, therefore, reduction of both acetyl-CoA concentration and pyruvate-to-glucose conversion occur, corresponding with the cessation of glycerol supply, observing a decrease in pyruvate carboxylase (PC) enzyme

However, when WAT is in an inflammatory process and insulin resistance, it constantly increases the supply of gluconeogenic substrates, such as non-esterified fatty acids (NEFAS), and glycerol favors hepatic glucose production [121]. In stages with normal insulin levels, fatty acids in the bloodstream compete with glucose to internalize cells independent of hyperglycemia; however when insulin concentration or activity is deficient, fatty acids contribute directly to the production of glucose [122]. The ectopic accumulation of fatty acids in liver increases the content of acetyl-CoA allosterically activating PC and increasing gluconeogenesis; this increase in glucose and the presence of pro-inflammatory cytokines lead to inad-

According to current knowledge of the importance of indirect insulin pathways in the liver to maintain the homeostatic glucose process, research groups will follow some therapeutic targets associated with the signaling pathways of G-proteincoupled receptors (GPCRs) [124] as well as inhibitors of the enzyme acetyl-CoA carboxylase [125, 126] for the treatment of metabolic diseases. Similarly there is evidence that proves that the diet with low calorie concentrations can reverse

The skeletal muscle is responsible for 70% of the elimination of total body glucose, associated with its capacity and energy need. Therefore, insulin sensitivity of skeletal muscle is critically important in maintaining homeostasis of blood glucose [128]. Many studies propose molecules related to the deterioration in insulin signaling; however, they agree that these molecules accumulate when the energy supply exceeds the demand in the body. Therefore, it suggests that the IR in the

equate insulin signaling in liver and subsequently, IR [123].

carboxykinase (PCK1) and glucose 6 phosphatase (G6PC) [116, 117].

*Adipose Tissue in Health and Disease DOI: http://dx.doi.org/10.5772/intechopen.90559*

#### *3.2.1 Liver*

*Obesity*

expression between the different miRs.

among individuals of the same species.

RT-PCR, in situ hybridization or northern blot.

broad view of the presence and regulation of miRs.

in gene regulation that are lost in biological noise.

rectly and therefore does not slow the lipolysis process.

similar binding sequences in the 3′UTR region for single or multiple miRs. These miRs exert their silencing function through two different mechanisms: translation inhibition (initiation or elongation) and target mRNA degradation. In the target genes for miRs, it is observed that 3′UTR regions have binding sites for multiple miRs; this suggests cooperation and redundancy of the effect on gene

Currently, there are 1917 human miRNAs listed in the miRNA database miRBase

The logical sequence in the integral investigation of miRs is firstly to identify the presence in a given sample. The experimental tools used to measure the expression profile of miRs have been by microarray analysis or deep sequencing, while the determination of the level of expression of individual miRs has been performed by

However, the investigations carried out can be categorized from two conceptual points, the determination of the level of expression in which the most used methodological tool is real-time PCR analysis and global expression assays. The former stand out for their specificity while confirming the latter, while the latter provide a

Properly identifying the functionality and level of expression of a specific miR is limited due to the high degree of sequence homology between some miRs and the size of the molecule; the parallel application of different molecular tools strengthens the identification or quantification process of the level of expression. However, an unfavorable factor is the combined regulation of multiple genes or small changes

Enhancing the work of performing research surrounding these novel gene regulators will advance our understanding of miRNAs and their specific functions and will augment the opportunities to safely follow them as therapeutic

Conventionally, insulin acts directly on the WAT under the cascade of the IRS1 axis, PI3K, and AKT, for glucose absorption, with a possible positive feedback of the phosphorylation of Ser388 from IRS2, by cyclin-dependent kinase 4 (CDK4) [114], culminating with lipolysis regulation. However, as described in previous sections of the chapter, inflammatory processes and alternative activation of macrophages favor the pathogenic adiposity in which the action of insulin is not carried out cor-

Although the mechanism of signaling pathways that links pathogenic adiposity to insulin resistance in skeletal muscle and liver has not been well defined due to the difficulty of modeling in vitro systems that allow cell coordination as in a complex organism, the process of understanding molecular bases has lagged behind the direct action of insulin in an organ or cell. The best way to associate it is the chronic surplus of energy that favors the accumulation of ectopic lipids in the liver and skeletal muscle that trigger the activation of pathways that impair insulin signaling, causing the decrease in glucose absorption in muscle cells and of glycogenesis in

From the extraction of plasma and blood serum miRs from human and mammalian animal samples, they have been proposed as diagnostic biomarkers in the diseases. The attributes that stand out are that the miRs extracted from the serum have stability, and the results in the quantification are reproducible and consistent

(http://www.mirbase.org), representing 1% of all genes in the human genome. These miRNAs are predicted to target aprox. 30% of the human gene pool.

**20**

liver [115]**.**

targets [113].

**3.2 IR in muscle and liver**

In a physiological stage with food withdrawal, the main source of glucose in the bloodstream is the liver. On the other hand, after absorption of nutrients by the intestine, the production of hepatic glucose should be interrupted in coordination with hyperinsulinemia.

The most assertive explanations of how insulin acts to promote glucose homeostasis by inhibiting both glycogenolysis and hepatic gluconeogenesis have focused on the canonical pathway of insulin interacting directly in the liver by activating the insulin receptor (InsR) and the substrate of insulin receptor (IRS) and the phosphoinositol 3-kinase signaling cascade (PI3K/Akt/mTOR pathway) by inhibiting transcription of the forkhead box class O-1FOXO1 factor and thus gene transcription and activation of gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase (PCK1) and glucose 6 phosphatase (G6PC) [116, 117].

However, it has been observed that suppression of hepatic glucose production is not totally dependent on the Akt activation pathway, for which remote insulin actions that interact indirectly with the physiological process of hepatic glucose have been studied. On one hand, the reduction of PCK1 and glucose 6-phosphatase (G6Pase) through cerebral insulin action activates the ATP-sensitive potassium channels (KATP) of hypothalamus and stimulate the vagal transmission and STAT3 activation [118, 119], blocking the *de novo* glucose formation by the liver and therefore regulating serum hyperglycemia.

On the other hand, insulin action in WAT suppresses lipolysis and reduces the fatty acids flow into the liver, therefore, reduction of both acetyl-CoA concentration and pyruvate-to-glucose conversion occur, corresponding with the cessation of glycerol supply, observing a decrease in pyruvate carboxylase (PC) enzyme activity [120].

However, when WAT is in an inflammatory process and insulin resistance, it constantly increases the supply of gluconeogenic substrates, such as non-esterified fatty acids (NEFAS), and glycerol favors hepatic glucose production [121]. In stages with normal insulin levels, fatty acids in the bloodstream compete with glucose to internalize cells independent of hyperglycemia; however when insulin concentration or activity is deficient, fatty acids contribute directly to the production of glucose [122]. The ectopic accumulation of fatty acids in liver increases the content of acetyl-CoA allosterically activating PC and increasing gluconeogenesis; this increase in glucose and the presence of pro-inflammatory cytokines lead to inadequate insulin signaling in liver and subsequently, IR [123].

According to current knowledge of the importance of indirect insulin pathways in the liver to maintain the homeostatic glucose process, research groups will follow some therapeutic targets associated with the signaling pathways of G-proteincoupled receptors (GPCRs) [124] as well as inhibitors of the enzyme acetyl-CoA carboxylase [125, 126] for the treatment of metabolic diseases. Similarly there is evidence that proves that the diet with low calorie concentrations can reverse hyperglycemia [127].

#### *3.2.2 Muscle*

The skeletal muscle is responsible for 70% of the elimination of total body glucose, associated with its capacity and energy need. Therefore, insulin sensitivity of skeletal muscle is critically important in maintaining homeostasis of blood glucose [128].

Many studies propose molecules related to the deterioration in insulin signaling; however, they agree that these molecules accumulate when the energy supply exceeds the demand in the body. Therefore, it suggests that the IR in the muscle not only has intrinsic problems as a reference. One of the main mechanisms proposed to elucidate the pathogenic process of IR in skeletal muscle is mitochondrial compromise due to the bioenergetic imbalance present mainly in pathological adiposity. However, the molecular pathways to describe this event are not entirely elucidated.

In the physiological process of insulin/IR interaction in skeletal muscle, you can activate two signaling pathways with the phosphorylation of IRS1 and, on the one hand, the PI3K/AKT pathway that induces glycogen synthesis and glucose uptake by recruiting the transporter protein of glucose (GLUT-4) to the plasma membrane, while the activation of the MAPK pathway favors the growth and differentiation of skeletal muscle [129].

The presence of pathological adiposity provides high concentrations of fatty acids and cytokines that activate signaling pathways linked to obesity that converge with insulin signaling. As plasma FFA increase, they accumulate in muscle. Intramuscular diacylglycerol (DAG) and ceramides levels rise, compounds that might act as second messengers in alternative signaling pathways that interfere with IRS-1 adequate phosphorylation [108, 130].

The presence of TAG and DG in muscle activates Ser307 phosphorylation in IRS-1, resulting in the activation of PKC-θ. These changes in turn result in a decrease in the tyrosine phosphorylation of IRS-1 and a lower activation of the PI3K associated with IRS-1, resulting in a decrease in insulin-stimulated glucose transport activity. Intramolecular lipids (IMCL) have been observed to be elevated when lipid oxidation is poor and lipid supply to the muscle is exceeded [120, 131, 132].

The bioenergetic imbalance favors mitochondrial beta oxidation, although incompletely which can increase the concentration of reactive oxygen species (ROS) mainly H2O2, this reactive species is responsible for the inhibition of PP2A causing the activation of JNK and ERK, and these inhibit serine phosphorylation in IRS1. When the energy demand is exceeded, skeletal muscle mitochondria stimulate lipid biosynthesis that redundantly increases the concentration of ROS and myocellular lipids [133–135].

Although the process by which ROS and fatty acids trigger insulin resistance is not yet elucidated, it can be deduced that energy imbalance is the fundamental key.

### **4. A new terminology: pathologic adiposity**

Total adipose mass, fat depot location, and particular AT type function are the predominant factors that explain high metabolic risk in individuals with obesity, since number, distribution, and leucocyte population differ between SCAT and VAT from lean and obese individuals; VAT has higher a macrophage number, and adipocyte size is smaller and has less lipid storage capacity. These differences suggest VAT can undergo subclinical inflammation and metabolic disease [136]; actually, central obesity associates with higher CVD, metabolic disorders, and early death, in contrast with gynecoid obesity at the expense of SCAT accumulation in the gluteofemoral region [13].

With the aforementioned, we can state that not every obese individual is affected by the common metabolic abnormalities associated with obesity. Approximately 10–25% of obese and a smaller fraction of morbidly obese persons are "metabolically healthy" (metabolically healthy obese, MHO), as they are insulin sensitive and normotensive and possess a favorable lipid profile; furthermore, they present less VAT and hepatic lipids and possess normal glucose metabolism. On the other hand, a subgroup of normal weight individuals suffers obesity characteristic metabolic abnormalities, whereby they are denominated as "metabolically healthy

**23**

**Figure 3.**

*Adipose Tissue in Health and Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.90559*

but with normal weight" (MONW). It is suggested that MHO individuals own a less detrimental metabolic profile and better prognosis compared to normal weight

that AT could undergo healthy remodeling and maintenance [140].

As stated before in this chapter, under acute caloric excess, enlarged adipocytes suffer hypoperfusion and mechanic stress owing to its surrounding ECM, which causes transient hypoxia and triggers angiogenesis and release of stress signals so

Nonetheless, obesity is a chronic caloric excess state, which means adipocyte enlargement surpasses angiogenesis, whereby hypoxia and stress signals perpetuate and cause fibrosis and cell death with eventual necrosis; this scenario causes local lipotoxicity, as ATM lipid buffering function is surpassed by the increased FFAs levels caused by overfeeding or adipocyte lipolysis and death [141, 142]. Thus, ATMs undergo metabolic activation, as lipids like palmitate are TLR-2/4 ligands, therefore initiating a proinflammatory response and polarization towards a M1 phenotype, losing all pro-homeostatic functions that we have previously discussed [143–145].

individuals with metabolic syndrome [137–139].

*A series of unfortunate events that leads to a pathologic adiposity status.*

*Adipose Tissue in Health and Disease DOI: http://dx.doi.org/10.5772/intechopen.90559*

*Obesity*

are not entirely elucidated.

skeletal muscle [129].

lipids [133–135].

the gluteofemoral region [13].

IRS-1 adequate phosphorylation [108, 130].

**4. A new terminology: pathologic adiposity**

muscle not only has intrinsic problems as a reference. One of the main mechanisms proposed to elucidate the pathogenic process of IR in skeletal muscle is mitochondrial compromise due to the bioenergetic imbalance present mainly in pathological adiposity. However, the molecular pathways to describe this event

In the physiological process of insulin/IR interaction in skeletal muscle, you can activate two signaling pathways with the phosphorylation of IRS1 and, on the one hand, the PI3K/AKT pathway that induces glycogen synthesis and glucose uptake by recruiting the transporter protein of glucose (GLUT-4) to the plasma membrane, while the activation of the MAPK pathway favors the growth and differentiation of

The presence of pathological adiposity provides high concentrations of fatty acids and cytokines that activate signaling pathways linked to obesity that converge with insulin signaling. As plasma FFA increase, they accumulate in muscle. Intramuscular diacylglycerol (DAG) and ceramides levels rise, compounds that might act as second messengers in alternative signaling pathways that interfere with

The presence of TAG and DG in muscle activates Ser307 phosphorylation in IRS-1, resulting in the activation of PKC-θ. These changes in turn result in a decrease in the tyrosine phosphorylation of IRS-1 and a lower activation of the PI3K associated with IRS-1, resulting in a decrease in insulin-stimulated glucose transport activity. Intramolecular lipids (IMCL) have been observed to be elevated when lipid oxida-

The bioenergetic imbalance favors mitochondrial beta oxidation, although incompletely which can increase the concentration of reactive oxygen species (ROS) mainly H2O2, this reactive species is responsible for the inhibition of PP2A causing the activation of JNK and ERK, and these inhibit serine phosphorylation in IRS1. When the energy demand is exceeded, skeletal muscle mitochondria stimulate lipid biosynthesis that redundantly increases the concentration of ROS and myocellular

Although the process by which ROS and fatty acids trigger insulin resistance is not yet elucidated, it can be deduced that energy imbalance is the fundamental key.

Total adipose mass, fat depot location, and particular AT type function are the predominant factors that explain high metabolic risk in individuals with obesity, since number, distribution, and leucocyte population differ between SCAT and VAT from lean and obese individuals; VAT has higher a macrophage number, and adipocyte size is smaller and has less lipid storage capacity. These differences suggest VAT can undergo subclinical inflammation and metabolic disease [136]; actually, central obesity associates with higher CVD, metabolic disorders, and early death, in contrast with gynecoid obesity at the expense of SCAT accumulation in

With the aforementioned, we can state that not every obese individual is affected by the common metabolic abnormalities associated with obesity. Approximately 10–25% of obese and a smaller fraction of morbidly obese persons are "metabolically healthy" (metabolically healthy obese, MHO), as they are insulin sensitive and normotensive and possess a favorable lipid profile; furthermore, they present less VAT and hepatic lipids and possess normal glucose metabolism. On the other hand, a subgroup of normal weight individuals suffers obesity characteristic metabolic abnormalities, whereby they are denominated as "metabolically healthy

tion is poor and lipid supply to the muscle is exceeded [120, 131, 132].

**22**

**Figure 3.**

*A series of unfortunate events that leads to a pathologic adiposity status.*

but with normal weight" (MONW). It is suggested that MHO individuals own a less detrimental metabolic profile and better prognosis compared to normal weight individuals with metabolic syndrome [137–139].

As stated before in this chapter, under acute caloric excess, enlarged adipocytes suffer hypoperfusion and mechanic stress owing to its surrounding ECM, which causes transient hypoxia and triggers angiogenesis and release of stress signals so that AT could undergo healthy remodeling and maintenance [140].

Nonetheless, obesity is a chronic caloric excess state, which means adipocyte enlargement surpasses angiogenesis, whereby hypoxia and stress signals perpetuate and cause fibrosis and cell death with eventual necrosis; this scenario causes local lipotoxicity, as ATM lipid buffering function is surpassed by the increased FFAs levels caused by overfeeding or adipocyte lipolysis and death [141, 142]. Thus, ATMs undergo metabolic activation, as lipids like palmitate are TLR-2/4 ligands, therefore initiating a proinflammatory response and polarization towards a M1 phenotype, losing all pro-homeostatic functions that we have previously discussed [143–145].

Furthermore, the other resident leucocytes will change in number and function as ATMs did, towards a Th1-type immune response.

The activation of NF-kB pathway with cytokine/chemokine release and the contribution of harmful metabolites (i.e., ceramide and sphingosine 1-phosphate, S1P) interfere with proper insulin signaling, therefore establishing a local AT IR [146–148].

After the AT IR is established, non-suppressive lipolysis now perpetuates and triggers high circulating FFA levels giving place to peripheral/systemic lipotoxicity: ectopic fat accumulation in liver and muscle; additionally, the proinflammatory cytokine, adipokine, and chemokine profile will circulate through the bloodstream, establishing metainflammation. Eventually, the high ectopic lipid concentration in this tissues will unleash similar detrimental effects that took place at AT, establishing now peripheral/systemic IR and dyslipidemia [132, 149].

The ensemble of this AT dysfunction and its harmful metabolic clinical repercussions is what we call pathologic adiposity: the adiposity status that determinates metabolic systemic dysfunction (IR and dyslipidemia), whether in an obese or normal weight individual, "metabolically unhealthy obese" (MUO), or "metabolically obese normal weight" (MONW) person, respectively (**Figure 3**).
