Domestic Animal Endocrinology 52 (2015) 60–70

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Phenomenon of leptin resistance in seasonal animals: the failure of leptin action in the brain M. Szczesna, D.A. Zieba* Department of Animal Biotechnology, Agricultural University in Krakow, 31-248 Krakow, Poland

a r t i c l e i n f o

a b s t r a c t

Article history: Received 12 January 2015 Received in revised form 8 March 2015 Accepted 8 March 2015

The core of the leptin resistance hypothesis promulgated several years ago to explain obesity as a result of environmental causes consists of 2 tenets: the extinction of leptininduced intracellular signaling downstream of leptin binding to the long form of the neuronal receptor LTRb in the hypothalamus and the impedance to leptin entry imposed at the blood–brain barrier (BBB). A recent comprehensive investigation concluded that a central leptin insufficiency associated with obesity can be attributed to a decreased efficiency of BBB leptin transport and not to leptin insensitivity within the hypothalamus. Interestingly, anorectic leptin’s effects are counteracted in some individuals by a natural resistance associated with hyperleptinemia, which is related to changes in hypothalamic sensitivity to leptin (eg, due to malnutrition, obesity, or seasonal variations due to daylength–dependent reproduction changes). In sheep, it has been observed that the hypothalamus is resistant to leptin in some periods, which is related to the adaptation of these animals to annual changes in energy supply and demand. However, a broad range of ambiguities exists regarding the implications that the intracellular signaling of signal transducer and activator of transcription-2/suppressor of cytokine signaling 3 (STAT2/ SOCS3) imparts central leptin resistance. Furthermore, several plausible alternative possibilities have been proposed, such as compensatory functional and anatomic reorganizations in the appetite regulating network, rearrangements in the afferent hormonal feedback signaling involved in weight homeostasis, and modifications in leptin transport to the hypothalamus across the BBB. Taken together, these observations suggest that the contention that impaired intracellular signaling downstream of leptin entry into the appetite regulating network expedites environmentally induced obesity remains unsubstantiated and requires further evidence. Furthermore, pregnancy decreases hypothalamic sensitivity to leptin (or other unknown mechanisms), and lactation can also alter the appetite-suppressing central activity of leptin. The objective of this review was to offer an approach to understanding (1) how information regarding nutritional status is transmitted to and interpreted within the hypothalamus in animals, with special attention on seasonally breeding animals and (2) whether central leptin resistance and/or leptin insufficiency in the hypothalamus favors the development of obesity. Ó 2015 Elsevier Inc. All rights reserved.

Keywords: Leptin resistance Leptin insufficiency Blood–brain barrier Pregnancy SOCS3 Seasonality

1. Introduction

* Corresponding author. Tel.: þ48 12 429 72 24; fax: þ48 12 429 75 47. E-mail address: [email protected] (D.A. Zieba). 0739-7240/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.domaniend.2015.03.002

In 1994, the pioneering work of Douglas Coleman at the Jackson Laboratory in Bar Harbor and Jeffrey Friedman of Rockefeller University changed opinions about obesity. Experiments with 2 strains of mice, genetically prone to

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obesity and diabetes, determined the mechanisms that drove the mice to overeat. The researchers discovered that one strain had a genetic defect in fat cells that secrete leptin [1]. Mice, like other animals, secrete leptin after a meal to suppress appetite and prevent overeating. The obese mice had a leptin deficiency and an insatiable appetite. However, 2 observations suggest that viewing obesity as a hormone disorder is too simplistic. Blood tests in obese individuals should indicate either decreased concentrations of the hormones that suppress food intake or increased concentrations of the hormones that increase appetite. However, the reverse is true. In general, obese individuals exhibit a paradoxically increased concentration of food intake– suppressing hormones, including leptin and insulin. Leptin secreted from peripheral adipose tissue acts centrally within the mammalian hypothalamus as an adipostat, which reduces appetite and promotes a negative energy balance [1]. However, the typically elevated circulating leptin concentrations in obese animals fail to act in this way, which reflects a state of leptin resistance [2]. To act centrally, leptin from circulating blood must first enter the brain, thereby passing through the blood–cerebrospinal fluid (blood-CSF) barrier at the choroid plexus (CP) and/or the blood–brain barrier (BBB) at the cerebral endothelium. Uotani et al [2] used Chinese hamster ovary cells stably expressing either long (LTRb) and short (LTRa) leptin receptor isoforms and suggested that leptin receptor desensitization, leptin-receptor signaling dysfunction, or a “defensive” decrease in leptin receptor expression may cause this reduced sensitivity. Myers et al [3] indicated that leptin transport across the BBB was disturbed. The loss of the anorectic properties of leptin is most likely not caused by a single mechanism, but rather, it results from a combination of factors. However, the critical mechanisms that underlie this process remain unclear. 2. Leptin signaling and leptin resistance Changes in leptin sensitivity occur predominantly at the hypothalamic level, but how this effect is mediated remains controversial. The mechanism receiving the most attention has been the inhibition of intracellular leptin signaling by the suppressor of cytokine signaling 3 (SOCS3). Based on the results of previous studies [4–7] and new findings [8], it has been suggested that 1 factor that contributes to leptin resistance is autosuppression, in which leptin stimulates the expression of SOCS3 factors that inhibit leptin signaling. The increased expression of SOCS3 in response to leptin may be a pivotal cause of the resistance and/or insensitivity to the anorectic action of this hormone, which represents a pathologic condition in obese individuals and a physiological phenomenon in seasonal animals, such as sheep during the long-day (LD) season. The occurrence of seasonal leptin resistance in sheep and other seasonally breeding species is associated with the adaptation to annual changes in energy supply and demand in these animals. However, the neuroendocrine basis of this phenomenon remains unknown. Our previous work [4–7] has indicated a role for SOCS3 factors in the modulation of the sensitivity of the hypothalamus and pituitary to leptin in vivo according to the season.

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In 2014, Asterholm et al demonstrated that resistin can cause central leptin resistance in mice through an increase in the circulating leptin concentrations. Murine studies support a direct role for resistin in insulin resistance. Asterholm et al [8] hypothesized that a chronically increased resistin concentration leads to leptin resistance and consequently a reduced sympathetic nervous system outflow. These effects may explain both the susceptibility to weight gain and, at least in part, the altered brown adipose tissue function, which includes reduced lipid clearance. The in vivo and in vitro measures of reduced hypothalamic leptin responsiveness in the presence of resistin support a novel unifying mechanism of central resistin-mediated metabolic effects [8]. 2.1. Mechanism of leptin action after leptin receptor binding The leptin receptor has a single membrane-spanning domain and exists in different LT isoforms (Ra, Rb, Rc, Rd, Re, and Rf), which are derived from alternative splicing of its messenger RNA (mRNA) [9]. All isoforms have similar ligand-binding domains; however, they differ at the C-terminus in the intracellular domain. The LTRb isoform, which contains a long intracellular domain, is the only isoform that possesses both of the protein motifs necessary for the activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway [2]. The leptin receptor lacks intrinsic enzymatic activity and mediates signals through the activation of receptor-associated intracellular JAKs. The leptin receptor homodimerizes after ligand binding and activates the JAK/STAT pathway. Phosphorylated STATs dimerize and subsequently translocate to the nucleus, where they bind to DNA and affect target gene transcription [10], including SOCS3. This system can be modulated by a large variety of cellular factors. Although the JAK2/STAT3 pathway has been considered the major signaling mechanism activated by the leptin receptor, mitogen-activated protein kinase and phosphatidylinositol3 kinase [11] have also been implicated in this phenomenon. It appears that SOCS3, which is an intracellular protein induced by leptin receptor activation, may mediate leptin resistance at the molecular level; these effects may primarily occur within the region of the arcuate nucleus (ARC), as it effectively blocks leptin signaling [12]. Despite the fact that proteins currently classified as SOCS were identified and characterized as negative regulators of cytokine signaling in the late 20th century [13], their role in the coordination of hormonal interactions remains poorly understood. In physiological conditions, the expression of SOCS mRNA in most tissues, with the exception of the brain, is rather low. However, some specific factors (eg, cytokines, growth factors, and hormones) can rapidly alter the level of SOCS expression. Leptin supplied through intraperitoneal or intravenous injection has been shown to result in a significant increase in SOCS3 expression in numerous hypothalamic nuclei in male leptin-deficient (ob/ob) mice [14]. A lack of changes in the SOCS3 mRNA levels in mice without functional leptin receptors, a rodent model of type 2 diabetes and obesity - leptin receptor deficient (db/db) mice confirms that this process is associated with the activation of leptin receptors [14]. In addition, there is evidence that

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implies SOCS3 has an important function within the pituitary. Recent experiments indicate that the SOCS3 expression level is also dependent on environmental factors, such as photoperiodic conditions and nutritional status [4,5]. 2.2. Seasonal animals as a model for SOCS-induced leptin resistance Seasonal rodents, such as the Siberian hamster (Phodopus sungorus) and field vole (Microtus agrestis), have previously been intensely investigated. Klingenspor et al [15] demonstrated that in the Siberian hamster, leptin reduces food intake more potently when administered during the short-day (SD) season compared with the LD season. In the Siberian hamster, the investigation of changes in SOCS3 mRNA levels in response to short-term fasting and longterm dietary restrictions, as well as the effects of exogenous leptin during the SD and LD seasons demonstrated that SOCS3 expression in the ARC was significantly increased during the LD season compared with the SD season in all experimental systems studied [15]. The lack of a leptin effect during the LD season in this experiment could result from a high endogenous, photoperiod-induced SOCS3 level, which, in turn, may have led to leptin resistance. These observations confirm the close relationship between SOCS3 and season-induced leptin resistance in these rodents. A lack of systemic responses to exogenous leptin and an upregulation of SOCS3 mRNA have also been identified in field voles after a rapid switch from lower to higher body mass associated with seasonal changes in day length [16]. Changes in the hypothalamic sensitivity to leptin have been reported in sheep at different times of the year [17,18]. Since 2005, studies by our laboratory have focused on leptin resistance caused by an increased SOCS3 expression in the hypothalamus. Sheep have a unique potential to serve as models for reversible leptin insensitivity because the ovine hypothalamus is resistant to leptin during some periods; this phenomenon is related to the adaptation of these animals to annual changes in energy supply and demand [17]. During the LD season, the concentration of leptin in blood plasma increases by 180% compared with the SD season [18]; however, this increase is not associated with the anorectic action of leptin. During this period, when there is an abundance of food and it is readily accessible, sheep exhibit an increased appetite and appear to be insensitive to the increased leptin concentrations that result from increased adiposity. Seasonal leptin resistance allows these animals to live in a changing climate and store energy that they will be able to use during periods of reduced food availability. In autumn and winter, sheep exhibit leptin sensitivity at the physiological level, and their appetite adjusts in proportion to their nutritional status. This paradox can be explained by the state of leptin resistance or leptin insensitivity that occurs during the LD season; however, the neuroendocrine basis of this phenomenon remains unknown. Studies conducted by our laboratory have indicated that intracerebroventricular (ICV) leptin infusions are also able to alter hypothalamic SOCS3 expression in sheep [4,5]. However, this effect was identified during LD but not SD conditions (Fig. 1), whereas in the pituitary, leptin affects

Fig. 1. SOCS3 messenger RNA expression (% of control) in the mediobasal hypothalamic arcuate nucleus brain region of sheep treated with an intracerebroventricular infusion of Ringer-Locke buffer (control) or leptin at a dose of 0.5 mg/kg body weight (BW) (leptin 1) or 1.0 mg/kg BW (leptin 2) during long-day (LD) and short-day (SD) photoperiods. SOCS3 expression was stimulated (P < 0.001) by leptin during the LD period but not the SD period [4]. * and ** denote differences from controls (P < 0.05 and P < 0.001).

this expression only during the SD season (Fig. 2). This finding explains the existence of leptin resistance in the hypothalamus with simultaneous maintenance of leptin sensitivity in the pituitary. This discovery may be the result of increased SOCS3 expression levels, and to some extent, may explain the phenomenon of a lack of hypothalamic sensitivity to the anorexic effects of leptin during the LD season. The results of these experiments demonstrate that leptin centrally infuses into the third ventricle (3V) of the brain and affects the expression of SOCS3 factors in seasonand tissue-dependent manners. These results suggest that central leptin infusion alters the expression of SOCS3 factors in sheep, which leads to alterations in hypothalamic and pituitary sensitivity to the actions of leptin. 3. Photoperiodic-dependent leptin concentration in seasonal breeding animals Apart from SOCS3, photoperiods can also affect leptin expression in numerous species, including sheep. Exposure of ovariectomized adult ewes to a long day length for 4 to

Fig. 2. SOCS3 messenger RNA expression (% of control) in the pituitaries of sheep treated with an intracerebroventricular infusion of Ringer-Locke buffer (control) or leptin at a dose of 0.5 mg/kg body weight (BW) (leptin 1) or 1.0 mg/kg BW (Leptin 2) during long-day (LD) and short-day (SD) photoperiods. * P < 0.05, ** P < 0.01 and *** P < 0.001 denote differences from the control [5].

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6 wk stimulated leptin release and expression in perirenal adipose tissue, and this effect was independent of any change in adipocyte number or feed intake [19]. A similar effect of long days on leptin expression was previously reported in Djungarian hamsters [20]. In lactating dairy cows, exposure to different photoperiodic conditions significantly affected the gene expression of leptin and its receptors in adipose tissue. Cows exposed to LD conditions (18:6) exhibited higher leptin expression compared with cows housed under neutral (12:12) or short day-length (6:18) conditions. In addition, expression of the LTRb was downregulated by SD conditions [21]. Bertolucci et al [22] reported on the circadian rhythms of leptin release from adipose tissue in sheep, showing a minimum hormone concentration occurring during the light phase and peak secretion observed during the dark phase. Moreover, the amplitude of these changes was higher during the SD [23]. The mechanisms involved in photoperiod-induced differences in adipose tissue leptin expression remain unknown. Direct effects of the sympathetic nervous system and interactions between melatonin and prolactin (PRL) have been suggested to play a role in this process [24]. In adipocyte cell membranes, many receptors mediate adipose tissue sensitivity to various hormonal factors. For example, in mammalian adipocytes, receptors for leptin [25], insulin [26], melatonin [27,28], PRL [29], and growth hormone [30] are present, suggesting that these hormones may directly regulate adipocyte activity, including their secretory activity.

3.1. Seasonality of leptin action In the last 2 decades, many factors affecting appetite and energy expenditure have been described. The effects of many of these factors are dependent on photoperiods. Melatonin, which is a biochemical indicator of changes in light conditions, is functionally and anatomically involved in the modulation of numerous interactions linked with adaption to changes in food intake caused by circadian and annual changes in the environment. Moreover, many other hormones involved in maintaining energy homeostasis are characterized by daily and annual fluctuations of their bloodstream concentrations. In temperate latitudes, sheep are seasonal breeders with reproductive activity controlled mainly by photoperiods. Nocturnal secretion of pinealderived melatonin provides information about day length, but neither the target brain sites for its action nor the neuropeptide circuits engaged by the melatonin signal are well defined [31]. Recently, attention has been focused in this process on the role of leptin, which has been strongly implicated as one of the major peripheral signals controlling body fat reserves and appetite in mammals. In numerous animal species, food intake and the amount of fat stored change over the course of the year. Melatonin can affect adipose tissue through sympathetic innervation. Neurons projecting directly into fat tissue from the suprachiasmatic nuclei (SCN), which are brain structures that are particularly rich in melatonin receptors, have been observed [32] and were confirmed by experiments performed with Siberian hamsters. Melatonin infusion into

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the SCN caused a reduction in fat mass analogous to the reduction observed during SD [33]. Furthermore, melatonin receptors have been observed in the dorsomedial hypothalamus and anterior hypothalamic area, but not in the ARC, in seasonal species [34]. The ARC theoretically rules out the possibility of direct melatonin effects on leptin signaling within the ARC, which is the primary site of LTRs in the brain. Colocalization of these receptors elsewhere has not yet been demonstrated; however, both melatonin and LTRs have been independently localized to the DMN. Morgan and Mercer [35] reported that neurons from the dorsomedial hypothalamus, SCN, and ARC project to the paraventricular nucleus (PVN). Adam and Mercer [31] proposed that melatonin could contribute to hypothalamic sensitivity to leptin by acting on the PVN region (the center of appetite regulation); thus, the PVN represents a site where melatonin and leptin feedback may be coordinated. Relative leptin insensitivity during LD may be necessary to prevent the observed increase in leptin concentrations, which could cause appetite reduction and thereby counteract photoperiod-driven increases in voluntary food intake and body weight (BW) [36]. Collectively, these observations imply a distinct system of regulation in which normal responses to leptin and energy deficits are overridden by photoperiods [36]. In addition to indirect melatonin effects, which occur through the nervous system, melatonin may directly modulate adipose tissue activity through the endocrine system by acting on specific adipocyte membrane receptors. In isolated rat adipocytes, melatonin inhibits basal and insulin-induced lipogenesis [37]. These observations were confirmed in studies by Zalatan et al [28], where melatonin inhibited isoproterenol-induced lipolysis, and this effect was blocked by pertussis toxin and a melatonin receptor agonist. Moreover, these melatonin effects were observed only in adipocytes derived from adipose tissue from the groin area and not from the epididymal region, suggesting a site-specific nature of these interactions [28]. Melatonin also enhanced leptin expression in primary rat adipocyte cultures in the presence of insulin; this effect was blocked by pertussis toxins and forskolin, which are known selective melatonin receptor antagonists [38]. Melatonin promoted this stimulation when it was added in a circadian-like manner (12:12) [38]. The role of melatonin in leptin secretion is still poorly understood. Several studies have reported that melatonin reduces blood leptin concentrations, whereas others have reported the opposite tendency. Pineal gland removal in rats was associated with an elevated concentration of leptin circulating in the bloodstream, and the application of exogenous melatonin reversed this effect [39]. Other studies indicate that the intraperitoneal injection of exogenous melatonin (1 mg) did not affect leptin secretion in rats when it was administered during the day; however, it slightly reduced leptin concentrations at night [40]. Exogenous melatonin also reduced leptin concentrations in Siberian hamsters [41]. In Syrian hamsters, high blood melatonin concentrations were associated with decreased leptin concentrations, and pineal gland removal resulted in increased leptin levels [42]. In contrast, in the seasonally breeding mink (Mustela vision), melatonin implantation in

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the fall was linked to a stimulating effect on leptin levels in the bloodstream [43]. Similarly, these hormones exhibited positive relationships with circadian rhythms in sheep [22]. However, regarding seasonal rhythms, the pattern observed for leptin concentrations is the opposite of the effect for melatonin release. Interestingly, several reports have indicated that leptin can affect melatonin secretion [44]. Recombinant ovine leptin can modulate melatonin release in ovine pineal gland explants in vitro (Fig. 3), and this effect is seasonally dependent [44]. Exogenous leptin inhibits melatonin secretion from pineal gland explants during long days and stimulates this process during short days [44]. A seasonal switch in ovine pineal gland sensitivity to leptin was also reported based on in vivo studies in sheep (Fig. 4). After ICV leptin infusion, stimulatory effects on melatonin secretion during SD and inhibitory effects during LD were observed [4]. 4. Leptin insufficiencydhypoleptinemia in the hypothalamus Studies in obese individuals indicate a decreased lumbar CSF-to-blood leptin concentration ratio, which indicates decreased blood-CSF leptin transfer. Using a large ovine model with a BW and adiposity similar to humans, Adam and Findlay [45] longitudinally explored the dynamics of endogenous leptin blood–brain transport in vivo from concurrent peripheral blood and CSF samples while the intrahypothalamic leptin sensitivity was also repeatedly tested by direct ICV administration. Adam and Findlay [45] demonstrated that CSF leptin concentrations initially increased with plasma levels as obesity developed in sheep; however, in contrast to plasma, the rate of increase in the CSF was not sustained. This finding reflects a decreased proportional transfer of leptin from the BBB with increased leptinemia. The reduced CSF:blood leptin concentration ratio in obese sheep endorses previous reports of reduced distal CSF:blood leptin in obese humans [46] and decreased blood-CSF leptin transfer in obese rats [47]. Adam and Findlay [45] demonstrated that some leptin

Fig. 3. Mean concentrations (standard error of the mean) of melatonin in control (medium-free) and leptin-treated (50 ng/mL) 3-h incubation of pineal gland explant cultures during short-day (SD) and long-day (LD) photoperiods. **Denotes a difference P < 0.001 from control (0 dose) during SD [44].

Fig. 4. Mean (standard error of the mean) serum concentrations of melatonin in Ringer-Locke buffer (control) and leptin-treated (0.5 mg/kg body weight [BW]) (leptin 1) or 1.0 mg/kg BW (leptin 2) ewes during short- (SD) and long-day (LD) photoperiods. Central leptin infusions increased mean concentrations of melatonin (P < 0.001) during the SD photoperiod in both treatment groups (L1 and L2) compared with controls (C). During LD, leptin decreased melatonin concentrations (P < 0.001) in leptin-treated sheep compared with controls in a dose-dependent manner [4]. *** denote difference from control (P < 0.001).

continued to enter the CSF of obese animals; however, the decreased magnitude of the increments within the brain compared with the periphery was insufficient to elicit the anorexic response. In contrast, the acute increase in the supraphysiological concentrations within the brain after ICV leptin injection was clearly sufficient to elicit the response. Obesity in the Adam and Findlay [45] ovine model was characterized by increased BW and external adiposity score and relatively increased “bad” (low-density lipoprotein) cholesterol concentrations in circulating plasma. Therefore, the results they presented support the hypothesis that the loss of the anorectic properties of central leptin associated with obesity is attributable to a decreased efficiency of blood–brain leptin transport and not to leptin insensitivity within the hypothalamus. 4.1. Diffusion of blood-borne factors into the brain is dependent on nutritional status In a recent study, Prevot et al [48] established a new physiological concept regarding the regulation of energy homeostasis by demonstrating that the nutritional status of an individual modulates the permeability of discrete blood hypothalamus barriers to circulating metabolic signals, which permits them to directly access a subset of ARC neurons. Many metabolic activities are coordinated by ARC neurons. This regulation is primarily mediated by the balance between anorexigenic neurons that express proopiomelanocortin and orexigenic neurons that express neuropeptide Y (NPY) and agouti-related protein (AgRP). For example, under fasting conditions, decreased systemic levels of nutrients (eg, glucose) and changes in related hormone levels (eg, decreased leptin and increased ghrelin) act to activate NPY/AgRP neurons and inhibit proopiomelanocortin neurons in the hypothalamus. These changes lead to a marked anabolic state within the hypothalamus, which translates into a potent stimulus for the animal to seek and ingest food. The ARC lies adjacent to the median eminence (ME), which contains a CSF barrier composed of

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tanycytes and specialized hypothalamic glia that line the floor of the 3V and extend processes to contact a specialized capillary plexus. The endothelial cells of this ME capillary plexus are unique in their fenestration, and their permeability enables the passive and rapid extravasation of most nutrients and metabolic hormones that circulate in the pituitary portal blood (ie, with molecular sizes less than 20 kDa). However, the restriction of this capillary fenestration to the ME, together with the occurrence of tight junction complexes between adjacent tanycytes that act as a physical barrier, sequesters these molecules within the ME and prevents their diffusion to the rest of the brain via the CSF in animals fed ad libitum [49]. In contrast, in fasting mice, dips in blood glucose levels, which are likely perceived by tanycytes with their glucosensing properties, trigger vascular endothelial growth factor (VEGF) A expression in these cells [50]. VEGF accumulation in the ME acts on endothelial VEGF receptor 2 to promote the fenestration of capillary loops that reach the ARC [51]. The ARC lies lateral to the 3V and immediately dorsolateral to the ME. VEGF induces endothelial hyperpermeability, and it is continuously and highly expressed in the CP, where the blood-CSF barrier is located [52]. In the ovine CP, 2 isoforms are expressed, including VEGF120 and VEGF164 [53]. VEGF plays an important role in the regulation of endothelial cell stability in the CP [54]. Nutritional status most likely modulates the plasticity of the blood-CSF barriers in this region; however, the pathophysiological implications of this reorganization of endothelial fenestration/tight junction complexes must be explored. In 2013, Prevot et al demonstrated that in mice fed ad libitum, the fenestrated blood vessels of the ME permit the local diffusion of macromolecules from the circulation, whereas vessels in the ARC properly exhibit BBB properties that block this diffusion. Thus, circulating metabolic signals whose levels are high in the fed state (eg, leptin and glucose) require BBB transport to access ARC neurons. Under these conditions, tight junctions between tanycytes line the ventricular wall of the ME, which prevent the diffusion of circulating factors into the 3V and CSF. During fasting or energy restriction, the levels of orexigenic hormones, such as ghrelin, increase with products of lipolysis, whereas leptin and glucose levels decrease. Concomitantly, some ME vessels that extend into the ARC become fenestrated, whereas the tight junction barrier along the 3V simultaneously extends dorsally. These changes allow the free diffusion of circulating signals that indicate energy restriction to ARC cells, including AgRP/NPY neurons that lie in the ventromedial ARC, whereas these substances are prevented from accessing the rest of the brain through the CSF [49]. The focal plasticity of this dual-faceted blood– hypothalamus barrier thus enhances the orexigenic and/or anabolic response to energy deficits. 4.2. Strategic leptin delivery to the brain Many newly discovered hormones, as exemplified by leptin, are peptides or regulatory proteins that must access receptors within the brain to exert their effects. Approximately 99.5% of the brain is protected by the BBB. Thus, many of these peptides and regulatory hormones depend

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on their ability to cross the BBB to access deep brain receptors. In many cases, as also exemplified by leptin, these peptides and regulatory proteins depend on transporters located at the BBB to enable access to the hypothalamus. When these transporters fail by allowing too much or too little hormone into the brain, disease can arise. Overall, modifications of leptin or its analogs would potentially have versatile uses in the development of therapeutic agents that target the brain and require transport across the BBB. Resistance at both the receptor level and the BBB becomes increasingly profound with advancing obesity. In some animal models, however, BBB resistance predominates in the earlier stages of obesity. The benefits of leptin administration to improve the success of weight loss programs for obese individuals have been recognized. Research efforts have also recognized the need to enhance leptin entry into the brain to improve its therapeutic efficacy, for example, by intrathecal injection [54], intranasal leptin administration, [55] or the modification of a molecule to produce a leptin with improved permeation across the BBB [56]. For example, TAT-leptin [57], P85-leptin [58], or MTS-leptin [59] have been identified and used as proteins capable of crossing the BBB independent of the leptin BBB transporter, which results in decreased feeding and weight loss in mice. Furthermore, because of the wide range of actions and strong biological activities of leptin, the effects of these proteins must be strictly controlled to prevent the disadvantageous consequence of excessive leptin receptor stimulation. The localization of SOCS3 mRNA in hypothalamic neurons and the significant induction of their expression in response to numerous factors, eg, resistin, indicate that SOCS3 plays a crucial role in the cytokine-induced regulation of neuroendocrine interactions. The previously discussed information suggests that SOCS3 proteins are important regulators that play a key role in feeding-induced or genetic-origin obesity and leptin resistance. These findings lead to the hypothesis that therapy that consists of a reduction in the levels of these proteins within the hypothalamus might be helpful in the treatment of obesity associated with reduced sensitivity to leptin. 5. PRL and pregnancy-induced leptin resistance The reproductive period, during which the demand for energy increases above average, is a significant challenge for an organism. The altered demand is especially noticeable in mammals living in the northern hemisphere because pregnancy and lactation require the correct balance between the physiological state of an organism and the external environmental conditions. Energy homeostasis maintenance for increased energy demand or limited possibilities of energy acquisition requires many physiological and endocrinologic adaptations. In general, it is accepted that reproduction and nutritional status are closely related. The leptin concentration in the blood is one of the main cues for energy stores, which influences entry into reproductive maturity in female mice [60] and rats [61], as well as stimulates sexual desire. Malnutrition negatively affects reproduction and has many effects, including a decrease in libido, a negative effect on pregnancy (implantation disorders and an increased rate of embryo resorption and miscarriages), and the complete

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inhibition of ovulation. Pregnancy and lactation are important factors that determine the amount of leptin in the bloodstream. Pregnancy is a state of physiological hyperphagia that occurs despite coexisting hyperleptinemia; therefore, it is a good model for the investigation of leptin resistance. Hyperleptinemia in pregnancy is not associated with decreased food intake. Leptin resistance during gestation occurs to fulfill the increasing requirements for nutrients and energy and is a maternal adaptation to pregnancy and subsequent lactation. In almost all species, the leptin level increases in the maternal circulation during pregnancy; a 25-fold increase in leptin concentration has been reported in mice [60] and rats [61]. Given the theory of the placental origin of this hormone, this large increase in the leptin concentration in mice does not appear to be correlated with adequate changes in maternal fat mass. In sheep, the concentration of leptin in the bloodstream increases in the first half of pregnancy [62] and is dependent on the number of fetuses, which thereby assumes higher values in the case of multiple fetuses [63]. The leptin concentration decreases in the second half of pregnancy, and a low concentration of the hormone is maintained during the first weeks of lactation [62]. Interestingly, in contrast to mice, leptin expression in the ovine placenta is very low [64]. In early lactation, leptin mRNA expression in adipose tissue is significantly reduced, and the concentration of the protein in the bloodstream is approximately 5 times lower in lactating compared with nonlactating sheep [65]. Ladyman and Grattan [65,66] reported that centrally administered leptin does not inhibit food intake during rat pregnancy and simultaneously decreases activated STAT3 levels in the VMH. These findings suggest that leptin resistance results from JAK/STAT pathway inhibition. Furthermore, Trujillo et al [67] identified a reduction in the level of STAT3 phosphorylation in pregnant rats after an intravenous injection of leptin. The study also demonstrated that in pregnant rats treated with ICV infusions of leptin, the hypothalamic level of SOCS3 increased compared with the nonpregnant rats, and the expression of LTRb at the end of pregnancy decreased. The investigation of pseudopregnant rats has produced interesting data regarding pregnancy-induced leptin resistance [68]. Pseudopregnancy is a state in which maternal-origin hormonal changes are similar to the changes identified in the first half of pregnancy; however, there are no hormones of placental origin. Moreover, similar to pregnant rats, pseudopregnant rats exhibit increased food intake. However, in contrast to pregnancy, leptin resistance does not occur during pseudopregnancy [69]. Trujillo et al [68] did not identify significant differences in the SOCS3 or LTRb levels in the hypothalamus of pseudopregnant compared with nonpregnant animals and determined that the ratio of CSF to serum leptin levels was similar in both groups. These data suggest that leptin resistance during rat pregnancy is induced by factors of placental origin, eg, placental leptin or lactogen. 5.1. Leptin, PRL, and energy homeostasis Pregnancy-induced and photoperiod-driven changes in food intake, BW, and accompanying leptin resistance play a very important role in the adjustment to variable demands for energy as part of maternal or seasonal adaptation.

Among the hormones that participate in these adaptive processes, PRL appears to play a major role in the adjustment process. In sheep, during both pregnancy and the LD season, when leptin resistance occurs, the PRL concentration is relatively high. Moreover, the regulation of energy homeostasis is a common point in the interaction between leptin and PRL. A long-term effect of the high concentration of PRL is an increase in appetite and BW in humans [70] and animals [71]; after stabilization of the PRL concentration, this effect is reversed [70]. PRL injected into the PVN exerts a stimulating effect on food intake, which confirms that this hormone is involved in the regulation of energy balance at the central nervous system level [72]. Furthermore, the presence of PRL receptors in the ARC, ventromedial nucleus, and PVN, which represent brain areas that regulate food intake and energy expenditure, supports this hypothesis [73,74]. Roy et al [74] demonstrated the coexpression of LTRs and PRL receptors in the rat brain. The interactions described in this section may become more important during pregnancy and lactation. 5.2. Potential role of PRL in leptin resistance Based on the variety of factors that influence SOCS3 expression and the large number of potential interactions that occur in organisms, the effect of other hormones on the modulation of the previously described endocrine relationship (also relative to the season) should not be ignored. Presumably, during LD, at least in hamsters, the SOCS3 gene is constitutively expressed at a high rate, regardless of the endogenous leptin concentration [21]. This finding supports the assumption that the maintenance of a high level of SOCS3 results from an interaction with a molecule other than leptin. Considering that the main cue from changes in day length are changes in the concentration of melatonin, this pineal hormone or other hormones of which the concentration in the bloodstream is highly dependent on the concentration of melatonin (eg, PRL) may be involved in the season-dependent modulation of SOCS3 expression. It has been demonstrated that SOCS3 is involved in the modulation of intracellular signal transduction pathways induced by PRL [75]. To our knowledge, our previous experiments [5] were the first to report the effect of exogenous PRL on SOCS3 expression in the ovine pituitary (Fig. 5). In the literature, there is no information regarding the effect of PRL on SOCS3 expression in sheep. Our experiments demonstrated that the effect of PRL on SOCS3 expression varies on an annual basis; exogenous PRL stimulated the SOCS3 expression during the LD period (March and May), but did not affect the SOCS3 mRNA levels in October when the day length is shorter (Fig. 6). Surprisingly, in pituitary explants collected and incubated with PRL in July, the SOCS3 mRNA levels were significantly decreased. Moreover, basal endogenous SOCS3 expression was also at its lowest in July [5], which coincides with the peak of the endogenous PRL concentration in the annual cycle in sheep [76]. We hypothesized that during this period, the PRL-induced expression of SOCS3 is blocked. It is possible that an organism needs the intensified effect of PRL to switch its physiological status from the LD to the SD season, which is characterized by different

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Fig. 5. The mean expression of SOCS3 messenger RNA (mRNA) (standard error) in 2-h ovine pituitary explants culture in the presence of prolactin (PRL) at a dose of 100 (PRL 1) or 300 ng/mL (PRL 2) at the indicated months. SOCS3 mRNA expression was reported in arbitrary units relative to cyclophilin mRNA expression. The mean value calculated for the control group was used as a calibrator. Expression levels were calculated by relative quantification (RQ) analysis. *P < 0.05 and **P < 0.01 compared with control [5].

reactions of the organism to endocrine-related processes. Investigations in rodents have provided interesting information regarding the action of PRL and leptin resistance. Rats subjected to the prolonged action of an ICV infusion of PRL were resistant to the anorectic effects of leptin administered in a similar manner and did not exhibit a reduction in appetite or weight loss, which is characteristic of individuals treated with exogenous leptin alone [77]. Moreover, during the second half of pregnancy in rats, when the endogenous PRL concentration is high, the anorectic effects of leptin administered via ICV infusions is reduced, which is similar to the expression of LTRb in the ventromedial nucleus [65,66]. These studies suggest that leptin resistance may be induced, at least in part, by a process caused by PRL receptor activation. As in LD photoperiods, increased PRL concentrations during pregnancy may be an important factor for SOCS3 activation, which leads, in turn, to a decrease in leptin sensitivity. Augustine and Grattan [78] demonstrated that the central infusion of PRL induces leptin resistance in pseudopregnant rats. SOCS3 may be a key factor in leptin-PRL crosstalk, which thereby participates in a potential mechanism through which the adjustment of energy homeostasis in response to the challenges of environmental (photoperiod) or physiological (pregnancy) changes is possible.

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Fig. 7. Mean SOCS3 messenger RNA (mRNA) expression (standard error) in ovine mammary gland explants collected from nonlactating ewes on long days (group 1), ewes on day 30 of lactation (group 2), ewes on day 56 of lactation (group 3), and nonlactating ewes on short days (group 4). SOCS3 mRNA expression was expressed in arbitrary units relative to cyclophilin mRNA expression, which was used as a reference gene. The mean value calculated for group 1 was used as a calibrator. Expression levels were calculated by relative quantification (RQ) analysis. Lower case letters denote differences from the control (P < 0.05); ** and *** denote differences (P < 0.01 and P < 0.001, respectively) between the other experimental groups [79].

5.3. Seasonal fluctuations in SOCS3 mRNA levels in ewe mammary glands Recently, we demonstrated in ovine mammary gland tissues that SOCS3 mRNA expression is dependent on the season and stage of lactation [79]. The highest expression of the examined factors was observed in the mammary glands of nonlactating sheep during SD, and the lowest levels were observed in ewes on day 30 of lactation (Fig. 7). The SOCS3 transcript levels observed in the tissues collected from nonlactating sheep during SD and LD were higher (74% and 41%, respectively) compared with the expression observed on day 30 of lactation. On day 56 of lactation, SOCS3 mRNA levels were similar to the levels observed in the udders of nonlactating sheep during LD. The results of this study demonstrated that in sheep, SOCS3 expression levels in mammary glands are strongly influenced by the stage of lactation and seasonality. Further studies are needed to study the role of SOCS3 in maintaining homeostasis in the mammary gland by modulating proliferation and functional development during pregnancy and tissue remodeling during involution. 6. Summary and conclusion

Fig. 6. Mean basal SOCS3 messenger RNA (mRNA) (standard error) expression in ovine pituitaries collected in different months (March, May, July, and October). SOCS3 mRNA expression was reported in arbitrary units relative to cyclophilin mRNA expression. The mean value for the pituitary isolated in March was used as the calibrator. Expression levels were calculated by relative quantification (RQ) analysis. **P < 0.01 compared with control [5].

In seasonal animals, intense research has been conducted to provide explanations for the relationships between hormones engaged in the regulation of reproduction, energy homeostasis, and metabolism and the processes controlled by these relationships. These studies have been conducted not only in theoretical but also in practical terms for the treatment of pathologic phenomena associated with endocrine dysfunction in animals or related to the economic viability of farming. Because of their strictly regulated adaptation to environmental conditions related to the plasticity of their endocrine system and the presence of

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physiological leptin resistance, sheep and other seasonal breeding animals represent a particularly interesting model for such studies. The observations described previously emphasize the close relationship that exists between photoperiod, which is a powerful factor that influences the course of many processes in those species; its main biochemical indicator, melatonin and the adipose-derived hormone leptin are associated with photoperiod-driven changes in intrahypothalamic and intrapituitary expression of SOCS3 mRNA. Furthermore, changes associated with leptin-mediated actions and SOCS3 signaling resulted in differential regulation of both melatonin and PRL secretion during the LD and SD seasons. Finally, season- and lactationdependent expression of SOCS3 mRNA was confirmed in ovine mammary glands, which suggests that SOCS3 protein may be involved in interactions between leptin and PRL. Because of the wide range of actions and strong biological activity of leptin, the effects of its action must be strictly controlled to prevent disadvantageous consequences of excessive stimulation of leptin receptors. The localization of SOCS3 mRNA in neurons of the hypothalamus and the fact that SOCS3 is significantly upregulated in response to numerous factors indicate that SOCS3 plays a crucial role in cytokine-induced regulation of neuroendocrine interactions. Taken together, findings demonstrate an abundance of functions performed by hormones engaged in the regulation of seasonal reproduction and energy homeostasis which form a close web of interactions and interrelationships. Acknowledgments This work was supported by a grant from the National Science Center 2013/09/B/NZ4/01532. References [1] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–32. [2] Uotani S, Bjørbaek C, Tornøe J, Flier JS. Functional properties of leptin receptor isoforms: internalization and degradation of leptin and ligand-induced receptor downregulation. Diabetes 1999;48: 279–86. [3] Myers Jr MG, Leibel RL, Seeley RJ, Schwartz MW. Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab 2010;11:643–51. [4] Zieba DA, Szczesna M, Klocek-Gorka B, Molik E, Misztal T, Williams GL, Romanowicz K, Stepien E, Keisler DH, Murawski M. Seasonal effects of central leptin infusion on secretion of melatonin and prolactin and on SOCS-3 gene expression in ewes. J Endocrinol 2008;198:147–55. [5] Szczesna M, Zieba DA, Klocek-Gorka B, Misztal T, Stepien E. Seasonal effects of central leptin infusion and prolactin treatment on pituitary SOCS-3 gene expression in ewes. J Endocrinol 2011;208:81–8. [6] Zieba DA, Szczesna M, Klocek-Gorka B, Williams GL. Leptin as a nutritional signal regulating an appetite and reproductive processes in seasonally- breeding ruminants. J Physiol Pharmacol 2008;59:7–18. [7] Szczesna M, Kirsz K, Kucharski M, Szymaszek P, Zieba DA. The seasonal interactions between leptin and GH and its effect on pituitary SOCS-3 gene expression in sheep. Health 2013;5:29–39. [8] Asterholm IW, Rutkowski JM, Fujikawa T, Cho YR, Fukuda M, Tao C, Wang ZV, Gupta RK, Elmquist JK, Scherer PE. Elevated resistin levels induce central leptin resistance and increased atherosclerotic progression in mice. Diabetologia 2014;57:1209–13. [9] Bjorbaek C, Uotani S, Da Silva B, Flier JS. Divergent signaling capacities of the long and the short isoforms of the leptin receptor. J Biol Chem 1997;272:32686–95.

[10] Banks AS, Davis SM, Bates SH, Myers Jr MG. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 2000;275:14563–72. [11] Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers Jr MG, Schwartz MW. Intracellular signaling. Key enzyme in leptin-induced anorexia. Nature 2001;413:794–5. [12] Bjorbak C, Lavery HJ, Bates SH, Olson RK, Davis SM, Flier JS, Myers MG. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J Biol Chem 2000;275:40649–57. [13] Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 1997;387:921–4. [14] Bjørbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1998;1:619–25. [15] Klingenspor M, Niggemann H, Heldmaier G. Modulation of leptin sensitivity by short photoperiod acclimation in the Djungarian hamster, Phodopus sungorus. J Comp Physiol B 2000;170:37–43. [16] Król E, Tups A, Archer ZA, Ross AW, Moar KM, Bell LM, Duncan JS, Mayer C, Morgan PJ, Mercer JG, Speakman JR. Altered expression of SOCS-3 in the hypothalamic arcuate nucleus during seasonal body mass changes in the field vole, Microtus agrestis. J Neuroendocrinol 2006;19:83–94. [17] Clarke IJ, Tilbrook AJ, Turner AI, Doughton BW, Goding JW. Sex, fat and the tilt of the earth: effects of sex and season on the feeding response to centrally administered leptin in sheep. Endocrinology 2001;142:2725–8. [18] Miller DW, Findlay PA, Morrison MA, Raver N, Adam CL. Seasonal and dose-dependent effects of intracerebroventricular leptin on LH secretion and appetite in sheep. J Endocrinol 2002;175:395–404. [19] Bocquier F, Bonnet M, Faulconnier Y, Guerre-Millo M, Martin P, Chilliard Y. Effects of photoperiod and feeding level on perirenal adipose tissue metabolic activity and leptin synthesis in the ovariectomized ewe. Reprod Nutr Dev 1998;38:489–98. [20] Klingenspor M, Dickopp A, Heldmaier G, Klaus S. Short photoperiod reduces leptin gene expression in white and brown adipose tissue of Djungarian hamsters. FEBS Lett 1996;399:290–4. [21] Bernabucci U, Basiricò L, Lacetera N, Morera P, Ronchi B, Accorsi PA, Seren E, Nardone A. Photoperiod affects gene expression of leptin and leptin receptors in adipose tissue from lactating dairy cows. J Dairy Sci 2006;89:4678–86. [22] Bertolucci C, Caola G, Foà A, Piccione G. Daily rhythms of serum leptin in ewes: effects of feeding, pregnancy and lactation. Chronobiol Int 2005;22:817–27. [23] Marie M, Findlay PA, Thomas L, Adam CL. Daily patterns of plasma leptin in sheep: effects of photoperiod and food intake. J Endocrinol 2001;170:277–86. [24] Lincoln GA, Clarke IJ. Photoperiodically-induced cycles in the secretion of prolactin in the hypothalamo-pituitary disconnected rams: evidence for translation of the melatonin signal in the pituitary gland. J Neuroendocrinol 1994;6:251–60. [25] Dyer CJ, Simmons JM, Matteri RL, Keisler DH. Leptin receptor mRNA is expressed in ewe anterior pituitary and adipose tissues and is differentially expressed in hypothalamic regions of well-fed and feed-restricted ewes. Domest Anim Endocrinol 1997;14:119–28. [26] Jarett L, Schweitzer JB, Smith RM. Insulin receptors: differences in structural organization on adipocyte and liver plasma membranes. Science 1980;210:1127–8. [27] Alonso-Vale MI, Andreotti S, Peres SB, Anhê GF, das Neves BorgesSilva C, Neto JC, Lima FB. Melatonin enhances leptin expression by rat adipocytes in the presence of insulin. Am J Physiol Endocrinol Metab 2005;288:E805–12. [28] Zalatan F, Krause JA, Blask DE. Inhibition of isoproterenol-induced lipolysis in rat inguinal adipocytes in vitro by physiological melatonin via a receptor-mediated mechanism. Endocrinology 2001;142:3783–90. [29] Ling C, Hellgren G, Gebre-Medhin M, Dillner K, Wennbo H, Carlsson B, Billig H. Prolactin (PRL) receptor gene expression in mouse adipose tissue: increases during lactation and in PRLtransgenic mice. Endocrinology 2000;141:3564–72. [30] Carter-Su C, Schwartz J, Kikuchi G. Identification of a high affinity growth hormone receptor in rat adipocyte membranes. J Biol Chem 1984;259:1099–104. [31] Adam CL, Mercer JG. Appetite regulation and seasonality: implications for obesity. Proc Nutr Soc 2004;63:413–9. [32] Bartness TJ, Song CK, Demas GE. SCN efferents to peripheral tissues: implications for biological rhythms. J Biol Rhythms 2001;16: 196–204.

M. Szczesna, D.A. Zieba / Domestic Animal Endocrinology 52 (2015) 60–70 [33] Bartness TJ, Powers JB, Hastings MH, Bittman EL, Goldman BD. The timed infusion paradigm for melatonin delivery: what has it taught us about the melatonin signal, its reception, and the photoperiodic control of seasonal responses? J Pineal Res 1993;15:161–90. [34] Morgan PJ, Mercer JG. Control of seasonality by melatonin. Proc Nutr Soc 1994;53:483–93. [35] Morgan PJ, Mercer JG. The regulation of body weight: lessons from the seasonal animal. Proc Nutr Soc 2001;60:127–34. [36] Tups A, Ellis C, Moar KM, Logie TJ, Adam CL, Mercer JG, Klingenspor M. Photoperiodic regulation of leptin sensitivity in the Siberian hamster, Phodopus sungorus, is reflected in arcuate nucleus SOCS-3 (suppressor of cytokine signaling) gene expression. Endocrinology 2004;145:1185–93. [37] Ng TB, Wong CM. Effects of pineal indoles and arginine vasotocin on lipolysis and lipogenesis in isolated adipocytes. J Pineal Res 1986;3: 55–66. [38] Alonso-Vale MI, Andreotti S, Borges-Silva Cd, Mukai PY, CipollaNeto J, Lima FB. Intermittent and rhythmic exposure to melatonin in primary cultured adipocytes enhances the insulin and dexamethasone effects on leptin expression. J Pineal Res 2006;41:28–34. [39] Canpolat S, Sandal S, Yilmaz B, Yasar A, Kutlu S, Baydas G, Kelestimur H. Effects of pinealectomy and exogenous melatonin on serum leptin levels in male rat. Eur J Pharmacol 2001;428:145–8. [40] Mastronardi CA, Walczewska A, Yu WH, Karanth S, Parlow AF, McCann SM. The possible role of prolactin in the circadian rhythm of leptin secretion in male rats. Proc Soc Exp Biol Med 2000;224: 152–8. [41] Korhonen T, Mustonen AM, Nieminen P, Saarela S. Effects of cold exposure, exogenous melatonin and short-day treatment on the weight-regulation and body temperature of the Siberian hamster (Phodopus sungorus). Regul Pept 2008;149:60–6. [42] Gündüz B. Daily rhythm in serum melatonin and leptin levels in the Syrian hamster (Mesocricetus auratus). Comp Biochem Physiol A Mol Integr Physiol 2002;132:393–401. [43] Mustonen AM, Nieminen P, Hyvärinen H, Asikainen J. Exogenous melatonin elevates the plasma leptin and thyroxine concentrations of the mink (Mustela vison). Z Naturforsch C 2000;55:806–13. [44] Zieba DA, Klocek B, Williams GL, Romanowicz K, Boliglowa L, Wozniak M. In vitro evidence that leptin suppresses melatonin secretion during long days and stimulates its secretion during short days in seasonal breeding ewes. Domest Anim Endocrinol 2007;33: 358–65. [45] Adam CL, Findlay PA. Decreased blood-brain leptin transfer in an ovine model of obesity and weight loss: resolving the cause of leptin resistance. Int J Obes (Lond) 2010;34:980–8. [46] Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 1996;348:159–61. [47] Oh TK, Li MZ, Kim ST. Gene therapy for diabetes mellitus in rats by intramuscular injection of lentivirus containing insulin gene. Diabetes Res Clin Pract 2006;3:233–40. [48] Prevot V, Langlet F, Dehouck B. Flipping the tanycyte switch: how circulating signals gain direct access to the metabolic brain. Aging 2013;5:332–3. [49] Skipor J, Thiery JC. The choroid plexus–cerebrospinal fluid system: undervaluated pathway of neuroendocrine signaling into the brain. Acta Neurobiol Exp 2008;68:414–28. [50] Szczepkowska A, M1ynarczuk J, Grochowalski A, Dufourny L, Thiéry JC, Skipor J. Effect of a two-week treatment with low dose of ortho-substituted polychlorinated biphenyls (PCB104 and PCB153) on VEGF-receptor system expression in the choroid plexus in adult ewes. Pol J Vet Sci 2012;15:621–8. [51] Maharaj AS, Walshe TE, Saint-Geniez M, Venkatesha S, Maldonado AE, Himes NC, Matharu KS, Karumanchi SA, D’Amore PA. VEGF and TGF-beta are required for the maintenance of the choroid plexus and ependyma. J Exp Med 2008;205:491–501. [52] Zhang C, Su Z, Zhao B, Qu Q, Tan Y, Cai L, Li X. Tat-modified leptin is more accessible to hypothalamus through brain-blood barrier with a significant inhibition of body-weight gain in high-fat-diet fed mice. Exp Clin Endocrinol Diabetes 2010;118:31–7. [53] Yaksh TL, Scott B, LeBel CL. Effects of continuous lumbar intrathecal infusion of leptin in rats on weight regulation. Neuroscience 2002; 110:703–10. [54] Schulz C, Paulus K, Jöhren O, Lehnert H. Intranasal leptin reduces appetite and induces weight loss in rats with diet-induced obesity (DIO). Endocrinology 2012;153:143–53. [55] Banks AS, Kim-Muller JY, Mastracci TL, Kofler NM, Qiang L, Haeusler RA, Jurczak MJ, Laznik D, Heinrich G, Samuel VT, Shulman GI,

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68] [69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

69

Papaioannou VE, Accili D. Dissociation of the glucose and lipid regulatory functions of FoxO1 by targeted knockin of acetylation-defective alleles in mice. Cell Metab 2011;14:587–97. Gertler A, Solomon G. Leptin-activity blockers: development and potential use in experimental biology and medicine. Can J Physiol Pharmacol 2013;91:873–82. Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS. Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 1997;99:391–5. Cheung CC, Thornton JE, Kuijper JL, Weigle DS, Clifton DK, Steiner RA. Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology 1997;138:855–8. Tomimatsu T, Yamaguchi M, Murakami T, Ogura K, Sakata M, Mitsuda N, Kanzaki T, Kurachi H, Irahara M, Miyake A, Shima K, Aono T, Murata Y. Increase of mouse leptin production by adipose tissue after midpregnancy: gestational profile of serum leptin concentration. Biochem Biophys Res Commun 1997;240:213–5. Chien EK, Hara M, Rouard M, Yano H, Phillippe M, Polonsky KS, Bell GI. Increase in serum leptin and uterine leptin receptor messenger RNA levels during pregnancy in rats. Biochem Biophys Res Commun 1997;237:476–80. Ehrhardt RA, Slepetis RM, Bell AW, Boisclair YR. Maternal leptin is elevated during pregnancy in sheep. Domest Anim Endocrinol 2001;21:85–96. Kulcsár M, Dankó G, Magdy HG, Reiczigel J, Forgach T, Proháczik A, Delavaud C, Magyar K, Chilliard Y, Solti L, Huszenicza G. Pregnancy stage and number of fetuses may influence maternal plasma leptin in ewes. Acta Vet Hung 2006;54:221–34. Thomas L, Wallace JM, Aitken RP, Mercer JG, Trayhurn P. Circulating leptin during ovine pregnancy in relation to maternal nutrition, body composition and pregnancy outcome. J Endocrinol 2001;169: 465–76. Sorensen A, Adam CL, Findlay PA, Marie M, Thomas L, Travers MT, Vernon RG. Leptin secretion and hypothalamic neuropeptide and receptor gene expression in sheep. Am J Physiol Regul Integr Comp Physiol 2002;282:R1227–35. Ladyman SR, Grattan DR. Region-specific reduction in leptininduced phosphorylation of signal transducer and activator of transcription-3 (STAT3) in the rat hypothalamus is associated with leptin resistance during pregnancy. Endocrinology 2004;145: 3704–11. Ladyman SR, Grattan DR. Suppression of leptin receptor messenger ribonucleic acid and leptin responsiveness in the ventromedial nucleus of the hypothalamus during pregnancy in the rat. Endocrinology 2005;146:3868–74. Trujillo ML, Spuch C, Carro E, Señarís R. Hyperphagia and central mechanisms for leptin resistance during pregnancy. Endocrinology 2011;152:1355–65. Grattan DR, Ladyman SR, Augustine RA. Hormonal induction of leptin resistance during pregnancy. Physiol Behav 2007;91:366–74. Greenman Y, Tordjman K, Stern N. Increased body weight associated with prolactin secreting pituitary adenomas: weight loss with normalization of prolactin levels. Clin Endocrinol (Oxf) 1998;48: 547–53. Byatt JC, Staten NR, Salsgiver WJ, Kostelc JG, Collier RJ. Stimulation of food intake and weight gain in mature female rats by bovine prolactin and bovine growth hormone. Am J Physiol 1993;264(6 Pt 1):E986–92. Sauvé D, Woodside B. Neuroanatomical specificity of prolactininduced hyperphagia in virgin female rats. Brain Res 2000;868: 306–14. Chiu S, Koos RD, Wise PM. Detection of prolactin receptor (PRL-R) mRNA in the rat hypothalamus and pituitary gland. Endocrinology 1992;130:1747–9. Pi XJ, Grattan DR. Differential expression of the two forms of prolactin receptor mRNA within microdissected hypothalamic nuclei of the rat. Brain Res Mol Brain Res 1998;59:1–12. Roy AF, Benomar Y, Bailleux V, Vacher CM, Aubourg A, Gertler A, Djiane J, Taouis M. Lack of cross-desensitization between leptin and prolactin signaling pathways despite the induction of suppressor of cytokine signaling 3 and PTP-1B. J Endocrinol 2007;195:341–50. Ling C, Billig H. PRL receptor-mediated effects in female mouse adipocytes: PRL induces suppressors of cytokine signaling expression and suppresses insulin-induced leptin production in adipocytes in vitro. Endocrinology 2001;142:4880–90. Misztal T, Romanowicz K, Barcikowski B. Melatonin modulation of the daily prolactin secretion in intact and ovariectomized ewes. Relation to a phase of the estrous cycle and to the presence of estradiol. Neuroendocrinol 1999;69:105–12.

70

M. Szczesna, D.A. Zieba / Domestic Animal Endocrinology 52 (2015) 60–70

[77] Naef L, Woodside B. Prolactin/leptin interactions in the control of food intake in rats. Endocrinology 2007;148:5977–83. [78] Augustine RA, Grattan DR. Induction of central leptin resistance in hyperphagic pseudopregnant rats by chronic prolactin infusion. Endocrinology 2008;149:1049–55.

[79] Szczesna M, Kirsz K, Kmiotek M, Zie˛ ba DA. Seasonal fluctuations in the steady-state mRNA levels of suppressor of cytokine signaling-3 (SOCS-3) in the mammary gland of lactating and non-lactating ewes. Small Rumin Res 2015;124: 101–4.