Teorías implícitas ϴ3 y su estatuto epistemológico fundante la cultura institucional,

This study has demonstrated that acute IH results in significant alterations in several variables associated with energy balance, adipokine release and activation of hypothalamic satiety signals. IH reduced body weight, active cycle food intake, and locomotion. These changes after IH were concomitant with a rise in plasma leptin and a reduction in plasma adiponectin, while adipose tissue had less leptin and more adiponectin protein expression after acute IH exposure. In ARC, acute IH induced phosphorylation of STAT3, reduced total ERK1/2 and phosphorylated ERK1/2, but did not significantly affect Ob-Rb or its negative regulator, SOCS3. Acute IH also induced activation, as determined by immediate early gene product FRA-1/2, of POMC-containing neurons of ARC and increased the protein expression of POMC in ARC. Taken together these suggest that IH induces significant alterations to body energy balance through changes in the secretion of leptin which exerts effects on satiety-inducing pathways within the hypothalamus.

The 8 h exposure to IH reduced body weight compared to Norm animals. However, by the following morning (16 h after IH), body weight change was found not to be different between the two groups. Unexpectedly, this body weight re-gain occurred despite a reduction in overnight food intake. Although the mechanism responsible for this re-gain in body weight is not clear, it is possible that the reduction in active cycle locomotion in IH-exposed animals may have contributed as a result of decreased energy expenditure. The regain of body weight in acute IH-exposed animals may be the result of alterations in

metabolism, as studies in rabbits have suggested that intermittent hypobaric hypoxia may lower circulating levels of thyroid hormones (Sawhney and Malhotra, 1990). Additionally, the reduction in food intake after acute IH was likely associated with the increased plasma leptin concentration, which occurred despite the lack of change in retroperitoneal or epididymal adipose tissue depot mass. It is known that leptin is correlated with adipose tissue content (Maffei et al., 1995). However, it has been reported that under certain pathophysiological challenges this balance can be altered (Kim and Scarpace, 2003). In this study, IH was a sufficient stimulus to elevate plasma leptin concentration and this may have accounted for the overnight reduction in food intake observed in these animals. Therefore, the actions and secretion of leptin appear to be independent of body weight changes induced by IH, while appearing inherently associated with IH. Taken together, these data can be interpreted to indicate that following acute IH, leptin may induce a state of satiety. As previously suggested, this may occur regardless of nutritional status (Levin et al., 1996; Rentsch et al., 1995). This finding is in contrast with reduced plasma concentration of leptin in individuals exposed to altitude-related hypoxia (Woolcott et al., 2002; Zaccaria et al., 2004). However, our findings occur following IH, rather than continuous hypoxia and under normobaric conditions, which may account for this difference. Consistent with this suggestion, it has been reported that IH can increase circulating leptin concentrations in mice (Li et al., 2005). It has been suggested that some IH models can induce sleep deprivation (Gozal et al., 2001). Sleep deprivation has been reported to reduce body weight and energy expenditure

(Vetrivelan et al., 2012), and a reduction (Vetrivelan et al., 2012) or no change (Bodosi et al., 2004) in leptin levels, with no changes in food intake (Barf et al., 2010; Vetrivelan et al., 2012). In humans, sleep deprivation has been shown to increase hunger and reduce leptin levels (Brondel et al., 2010; Spiegel et al., 2004). As well, corticosterone levels in the acute IH-exposed rats was not significantly different from Norm-exposed animals, if IH induced sleep deprivation in these animals, it would be expected that corticosterone levels would higher than controls (Tartar et al., 2009). Taken together, these data would suggest that it was unlikely that sleep deprivation played a significant role in the leptin-feeding responses observed in this study during acute IH.

Adipose tissue leptin content was found to be less in acute IH conditions. This, coupled with the finding of elevated plasma leptin concentrations, suggests an increase in the secretion of the adipokine by adipose tissue. Adipocytes have been demonstrated to increase their secretion of leptin in response to hypoxia (Famulla et al., 2012), and IH caused a sustained hypoxia in adipose tissue (Reinke et al., 2011). Taken together, these findings suggest that adipose tissue hypoxia resulting after acute IH in this study may have increased the release of leptin from adipocytes. Conversely, adiponectin had a lower circulating level, though an increased amount of the protein was found within adipocytes. This is consistent with previous studies showing that hypoxia causes a reduction in adipocyte secretion of the adipokine (Famulla et al., 2012). The changes in circulating levels of adipokines as seen in this study, induces a higher leptin:adiponectin ratio, perhaps as a result of altered adipocyte secretion as a

result of IH. An increase in leptin:adiponectin ratio is a commonly used measure associated with cardiometabolic disease (Satoh et al., 2004; Kotani et al., 2005). The alterations observed in circulating adipokine concentrations, as seen during IH in this study, are consistent with those found in individuals suffering from obesity (Dagogo-Jack et al., 1996) and obstructive sleep apnea (Hargens et al., 2013), of which IH is a major component.

Leptin action in ARC reduces food intake through activation of intracellular signaling pathways associated with Ob-Rb (Peters et al., 2007; Scarpace et al., 2007). The primary pathway associated with leptin’s satiety-inducing effects is

the phosphorylation of STAT3 in the rat (Ladyman and Grattan, 2004). Homodimerization of pSTAT3 results in translocation of the transcription factor to the nucleus of the affected cell. This induces transcription of several genes, such as Pomc and immediate early genes, including Fra-1 (Bousquet et al., 2000). Our results show that after acute IH, POMC protein content within ARC increases. This finding is supported by the observations of increased Pomc mRNA in response to leptin (Mizuno et al., 1998). The effect of leptin on specific neurons within ARC is thought to be dependent on the phenotype of the neurons within this region. Leptin has been shown to increase the firing rate of POMC- containing neurons (Cowley et al., 2001; Wang et al., 2008), while inhibiting the activity of neurons expressing neuropeptide Y (van den Top et al., 2004; Wang et al., 2008). Increased POMC in the hypothalamus induces hypophagia (Zhang et al., 2011), and we have found that acute IH induces both an increase in ARC POMC, as well as hypophagia. Our findings show that the IH leads to activation

of POMC-containing neurons within this region as it was found that a larger number of POMC neurons in ARC expressed the immediate early gene product FRA-1/2. The finding of increased FRA-1/2 expression in cells has been used to indicate alterations in neuronal activity, including depolarization under a variety of conditions, including IH (Messenger et al., 2012). These findings are further supported by the observation of transcriptional upregulation of satiety genes within the hypothalamus following chronic IH (Volgin and Kubin, 2006).

In summary, acute IH results in reductions in body weight, food intake and locomotion, and can alter the release of adipokines that regulate food intake from adipose tissue. Intracellular signaling pathways that are normally associated with satiety signaling were elevated in response to IH and this likely lead to the increased activity of POMC-containing neurons within ARC. These findings suggest that acute IH may result in altered body energy balance possibly through activation of hypothalamic pathways.