**2.1. Leptin**

214 Thyroid Hormone

interleukin 6.

the adipokines changes observed in obesity [10].

proinflammatory adipokines production - mainly TNF-α - and antagonistic on adiponectin. These substances lead to insulin resistance, reducing the lipogenic action of insulin in adipocytes, which results in higher rates of lipolysis in the adipose tissue [8, 9]. On the other hand, calorie restriction affects the regulation of adipose tissue gene expression, normalizing

**Figure 1.** Adapted from van Kruijsdijk et al, 2009 [6]. In obesity the hypertrophic and hyperactive adipocytes initiate the production of MCP-1, which attract macrophages into the adipose tissue, increasing proinflammatory adipokines production (mainly TNF-α) and decreasing adiponectin production, leading to insulin resistance and inflammation. The weight loss process revert this alterations, improving insulin resistance and inflammation. FFA: fatty free acids; PAI1: Plasminogen activator inhibitor 1; TNFα: tumor necrosis factor-α; MCP1: monocyte chemoattractant protein 1; IL6:

In this chapter will be revised about the influence of thyroid hormones on adipokines in obesity and weight loss. Also will be discussed the physiological role of adipokines as well

The adipose tissue is considered an endocrine organ and shows great dynamism. Since 1940 there is a hypothesis that adipose tissue has signals to communicate with other tissues [11], but only later was shown that this tissue is able to synthesize and secrete a large number of protein factors (which also act as cytokines) collectively called adipokines. These adipokines, in most part, are related, directly or indirectly, in processes involving atherosclerosis, hypertension, insulin resistance (IR) and type 2 diabetes (DM2), dyslipidemia, ie, represent the link between adiposity, metabolic syndrome and cardiovascular diseases [12-15]. Among these is Leptin, Resistin, Adiponectin, and others such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), acylation stimulating protein (ASP) and factors involved in the renin-

as the effect of obesity and weight loss on the adipokines.

**2. Adipokines physiological role** 

angiotensin system (RAS).

With its gene identified in 1994 [16] leptin is the adipokine most studied and thenceforth it has been identified more than 30 biochemical products secreted by adipocytes. Leptin is a peptidic hormone with 167 amino acids and 16kDa of molecular weight and synthesized from the "ob" gene in adipocytes, being more common in subcutaneous adipose tissue than in visceral fat [17]. Besides to be considered an important lipostate, or energy balance regulator according to body fat mass in long-term [18, 19] has been implicated in the regulation of immune, respiratory and reproductive systems [20]. The term Leptin comes from Greek "leptos" which means "thin" due to the fact that this protein lead to increased energy expenditure and act on satiety signals in hypothalamus, reducing caloric intake [21].

The expression and circulating leptin levels are controlled by a number of factors that may increase its secretion (insulin, glucocorticoids, TNF-α, estrogens, thyroid hormone and CCAAT/enhancer-binding protein-alpha) or decrease (Beta3-adrenergic activity, androgens , free fatty acids, GH, and peroxisome proliferator-activated receptor-gamma agonists) depending on the physiological assembly expressed by the body, especially on satiety and energy intake [22].

When circulating this adipokine reaches various body tissues as pancreas, increasing insulin secretion; liver, causing a satiety sensation by the increase in glucose production and increasing energy expenditure; hypothalamus, increasing stimulation of hypothalamicpituitary-adrenal axis, and decreasing the stimulus of hypothalamic-pituitary-thyroid and hypothalamic-pituitary-gonadal axis; muscle tissue, increasing glucose uptake and metabolism [23].

Many of the effects of leptin result from their actions on the central nervous system, particularly in the hypothalamus, which acts in satiety and appetite regulation. Reaching these tissues after crossing the blood-brain barrier, leptin acts in the arcuate nucleus where there is a large concentration of leptin receptors, when binding to reduce the action of neurons that use neuropeptide Y (NPY) signaling and agouti-related protein (ARGP). NPY is a peptide of 36 amino acids, synthesized mainly in the arcuate nucleus, which projects to the paraventricular nucleus, ventromedial, perifornical and lateral, also involved in energy balance regulation. It is the most potent orexigenic. The ARGP also synthesized in the arcuate nucleus, also is projected to paratentricular nucleus, ventromedial and lateral, acting as a melanocortin system analogue on receptors MC-3 and MC-4, stimulating food intake. Leptin acts by decreasing the activity of these orexigenics signals, inhibiting food intake and increasing energy expenditure by activating the sympathetic nervous system [24, 25]. Also in the hypothalamus, leptin activates neurons pro-opiomelanocortin (POMC) producing alpha-melanocyte stimulating hormone (alpha-MHS). All substances expressed in this system are anorexigenics, ie, act on reducing food intake [14]. This product acts on malanocortin-4 receptors and also on neurons that express cocaine and amphetamineregulated transcript (CART). POMC/CART neurones also have projections to the lateral hypothalamus and paraventricular nucleus, with a reciprocal innervation of these nuclei to the arcuate nucleus. Both alpha-MSH and CART are potent anorexigenic agents. The nucleus tractus solitarius (NTS) participates in the satiety control, involved in the end of food intake process. Afferent inputs related satiety signals include neurological vagus nerve and sympathetic system associated with chemical signals such as endocrine factors of gut cholecystokinin. There are many interconnections between hypothalamic nuclei including the paraventricular nucleus and the NTS (Figure 2).

Obesity and Weight Loss: The Influence of Thyroid Hormone on Adipokines 217

In the immune system the leptin receptor are expressed in hematopoietic cells, where leptin produced by adipocytes stimulates the normal growth of myeloid and erythroid [14]. In addition, leptin synergistically acts with other cytokines by increasing the proliferation of

Leptin effects on reproduction are varied and the target organs range of hypothalamus, ovary and endometrial. In the hypothalamic-pituitary axis there is a stimulatory effect [29]. Its levels have a circadian and ultradian cycle, and these variations are associated with varying levels of luteinizing hormone (LH) and estradiol, informing to the brain about the critical fat stores necessary for secretion of luteinizing releasing hormone and activation of hypothalamic-pituitary-gonadal axis [30]. The amount of leptin released in the brain is greater in women than in men, suggesting that women may be more resistant to the leptin action and require higher levels to achieve an appropriate response [31]. It is known that leptin, in ovaries, may affect the menstrual cycle by a direct inhibitory effect on the follicles development [29]. Leptin may still have an important role in the early stages of cleavage and embryonic development [32], in the fetal growth regulation and development, hematopoiesis and angiogenesis, as leptin receptors were found in syncytiotrophoblast, suggesting that leptin may play an important role in fetal endocrine function of fetoplacental unit [33]. In addition, leptin may play a central role in other target organs for reproduction, such as endometrial and mammary gland, influencing important functions

In the respiratory system leptin acts as a growth factor in the lung and as a modulator in the mechanisms of breathing central control. Leptin levels are elevated in patients with sleep

For hypothalamic-pituitary-thyroid axis leptin acts on the expression of thyrotropinreleasing hormone (TRH). Mice *in vitro* and *in vivo* study has demonstrated that leptin stimulates neurons directly in the paraventricular nucleus, which express TRH, increasing proTRH expression [35]. During fasting, the prohormone convertases 1 and 2 (PC1 and PC2) are decreased and leptin showed to restore PC1 and PC2 to pre-fasting levels [36]. Studies in rodents have shown that calorie restriction rapidly suppresses TRH expression in the paraventricular nucleus, leading to decreased thyroxine (T4) and triiodothyronine (T3) levels

Both partial and complete deficiency of leptin is associated with hypothyroidism. Ob/ob mice exhibit hypothyroidism at birth [39] and normal mice have decreased T4 levels during fasting [38]. Individuals with congenital leptin deficiency have a disorganized TSH secretion, suggesting that leptin may regulate the pulsatile characteristics of TSH and the circadian cycle [40]. In women with hypothalamic amenorrhea leptin treatment significantly increased free T3 and free T4, however did not affect TSH levels [41]. The lack of significant changes in TSH levels in many studies may be due to pulsatile nature of this hormone, but leptin can directly stimulate the T4 release from the thyroid gland and/or increase TSH

apnea, independent of body fat, being associated with leptin resistance [14].

leukocytes, specifically T4 cells.

including lactation and prevention of misbirth [34].

[37], and leptin can reverse these changes [38].

bioactivity [42, 43].

**Figure 2.** Food intake regulation by leptin at arcuate nucleus level. NPY: Neuropeptide Y; AGRP: Agouti-related protein; POMC: Pro-opiomelanocortin; CART: Cocaine and amphetamine-regulated transcript.

Among the actions taken by other hypothalamic nuclei in relation to energy homeostasis, can be highlight the ventromedial nucleus as a satiety center, lateral hypothalamus as the center of hunger and paraventricular nucleus on increased energy expenditure effects, as production of corticotropin releasing hormone and thyrotropin releasing hormone, activators the sympathetic nervous system. In perifornical nucleus, there is production of peptides termed orexins A and B, which act in the ventromedial nucleus and inhibits satiety and increase food intake. These areas receive nucleus axons of neurons in the arcuate nucleus, POMC/CART and NPY/ARGP, being considered as secondary action areas of leptin (downstream) [14, 26]. The leptin role in the CNS as a regulator is thus triggering mechanism (cascading effect), in order to stimulate or inhibit substances that act directly or indirectly in the hypothalamic areas involved in energy balance control.

In addition to their central effects, leptin also interacts with numerous peripheral tissues. Essentially, there are two major isoforms of leptin receptor, a long isoform which is required for full stimulation of the janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, and the short isoforms which result in the activation of JAK2 but not STAT. In skeletal muscle, for example, there are the two isoforms but the expression of short isoform is greater than the long one, making the leptin signalization in skeletal muscle activate various kinases including PI3-kinase, Akt (or PKB), PKC, MAP kinase kinase and Jun ERK [27, 28].

In the immune system the leptin receptor are expressed in hematopoietic cells, where leptin produced by adipocytes stimulates the normal growth of myeloid and erythroid [14]. In addition, leptin synergistically acts with other cytokines by increasing the proliferation of leukocytes, specifically T4 cells.

216 Thyroid Hormone

transcript.

Jun ERK [27, 28].

nucleus tractus solitarius (NTS) participates in the satiety control, involved in the end of food intake process. Afferent inputs related satiety signals include neurological vagus nerve and sympathetic system associated with chemical signals such as endocrine factors of gut cholecystokinin. There are many interconnections between hypothalamic nuclei including

**Figure 2.** Food intake regulation by leptin at arcuate nucleus level. NPY: Neuropeptide Y; AGRP: Agouti-related protein; POMC: Pro-opiomelanocortin; CART: Cocaine and amphetamine-regulated

indirectly in the hypothalamic areas involved in energy balance control.

Among the actions taken by other hypothalamic nuclei in relation to energy homeostasis, can be highlight the ventromedial nucleus as a satiety center, lateral hypothalamus as the center of hunger and paraventricular nucleus on increased energy expenditure effects, as production of corticotropin releasing hormone and thyrotropin releasing hormone, activators the sympathetic nervous system. In perifornical nucleus, there is production of peptides termed orexins A and B, which act in the ventromedial nucleus and inhibits satiety and increase food intake. These areas receive nucleus axons of neurons in the arcuate nucleus, POMC/CART and NPY/ARGP, being considered as secondary action areas of leptin (downstream) [14, 26]. The leptin role in the CNS as a regulator is thus triggering mechanism (cascading effect), in order to stimulate or inhibit substances that act directly or

In addition to their central effects, leptin also interacts with numerous peripheral tissues. Essentially, there are two major isoforms of leptin receptor, a long isoform which is required for full stimulation of the janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, and the short isoforms which result in the activation of JAK2 but not STAT. In skeletal muscle, for example, there are the two isoforms but the expression of short isoform is greater than the long one, making the leptin signalization in skeletal muscle activate various kinases including PI3-kinase, Akt (or PKB), PKC, MAP kinase kinase and

the paraventricular nucleus and the NTS (Figure 2).

Leptin effects on reproduction are varied and the target organs range of hypothalamus, ovary and endometrial. In the hypothalamic-pituitary axis there is a stimulatory effect [29]. Its levels have a circadian and ultradian cycle, and these variations are associated with varying levels of luteinizing hormone (LH) and estradiol, informing to the brain about the critical fat stores necessary for secretion of luteinizing releasing hormone and activation of hypothalamic-pituitary-gonadal axis [30]. The amount of leptin released in the brain is greater in women than in men, suggesting that women may be more resistant to the leptin action and require higher levels to achieve an appropriate response [31]. It is known that leptin, in ovaries, may affect the menstrual cycle by a direct inhibitory effect on the follicles development [29]. Leptin may still have an important role in the early stages of cleavage and embryonic development [32], in the fetal growth regulation and development, hematopoiesis and angiogenesis, as leptin receptors were found in syncytiotrophoblast, suggesting that leptin may play an important role in fetal endocrine function of fetoplacental unit [33]. In addition, leptin may play a central role in other target organs for reproduction, such as endometrial and mammary gland, influencing important functions including lactation and prevention of misbirth [34].

In the respiratory system leptin acts as a growth factor in the lung and as a modulator in the mechanisms of breathing central control. Leptin levels are elevated in patients with sleep apnea, independent of body fat, being associated with leptin resistance [14].

For hypothalamic-pituitary-thyroid axis leptin acts on the expression of thyrotropinreleasing hormone (TRH). Mice *in vitro* and *in vivo* study has demonstrated that leptin stimulates neurons directly in the paraventricular nucleus, which express TRH, increasing proTRH expression [35]. During fasting, the prohormone convertases 1 and 2 (PC1 and PC2) are decreased and leptin showed to restore PC1 and PC2 to pre-fasting levels [36]. Studies in rodents have shown that calorie restriction rapidly suppresses TRH expression in the paraventricular nucleus, leading to decreased thyroxine (T4) and triiodothyronine (T3) levels [37], and leptin can reverse these changes [38].

Both partial and complete deficiency of leptin is associated with hypothyroidism. Ob/ob mice exhibit hypothyroidism at birth [39] and normal mice have decreased T4 levels during fasting [38]. Individuals with congenital leptin deficiency have a disorganized TSH secretion, suggesting that leptin may regulate the pulsatile characteristics of TSH and the circadian cycle [40]. In women with hypothalamic amenorrhea leptin treatment significantly increased free T3 and free T4, however did not affect TSH levels [41]. The lack of significant changes in TSH levels in many studies may be due to pulsatile nature of this hormone, but leptin can directly stimulate the T4 release from the thyroid gland and/or increase TSH bioactivity [42, 43].
