Female Gender Exacerbates Respiratory Depression in  Leptin-deficient Obesity

Polotsky, Vsevolod Y.; Wilson, Jessica A.; Smaldone, Marc C.; Haines, Abby; Hurn, Patricia D.; Tankersley, Clarke G.; Smith, Philip L.; Schwartz, Alan R.; O’Donnell, Christopher P.

doi:10.1164/ajrccm.164.8.2101100

Cited by 58 publications

(50 citation statements)

References 28 publications

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“…We did not study other characteristics of obesity, but obesity is a state of sufficient magnitude to produce adverse health consequences, such as type 2 diabetes and hypertension. We do not know why only females have a higher body weight; however, there are many differences between the sexes that can affect obesity; it has been reported that sex hormones influence obesity (40), that the association between body mass index and lipids͞lipoproteins is stronger in females than in males (41), and that leptin-deficient obesity is affected by female sex (42). The finding that mice generated by culture in FCS or by micromanipulation (nuclear transfer) are susceptible to obesity (43,44) is consistent with a supposed phenotypic influence by preimplantation in vitro procedures.…”

Section: Discussionmentioning

confidence: 99%

Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes, development, and behavior

Fernández‐González

Moreira

Bilbao

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

354

271

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The long-term developmental and behavioral consequences of mammalian embryo culture are unknown. By altering the culture medium with the addition of FCS, we wanted to determine whether mouse embryos cultured under suboptimal conditions develop aberrant mRNA expression of imprinting genes at the blastocyst stage and whether fetal development, growth, and behavior of adult mice are affected. One-cell embryos obtained from superovulated female B6CBAF1 mice were cultured for 4 days in K ؉ -modified simplex optimized medium in the presence of either 10% FCS or 1 g͞liter BSA. After embryo transfer, born animals were submitted to several developmental and behavior tests. The mRNA expression of some imprinting genes was significantly affected in blastocysts cultured in the presence of FCS. Two of the eight measures of preweaning development and some specific measures of neuromotor development, such as the walking activity, were delayed in the group originated with FCS. After 34 weeks, the weight of female mice cultured in vitro in the presence of FCS was significantly higher than controls. In addition, the locomotion activity of mice was altered at 5 and 15 months. Anatomopathological and histological analysis of animals at 20 months of age showed some large organs and an increase in pathologies. We have found that mice derived from embryos cultured with FCS exhibited specific behavioral alterations in anxiety and displayed deficiencies in implicit memories. Our data indicate that long-term programming of postnatal development, growth, and physiology can be affected irreversibly during the preimplantation period of embryo development by suboptimal in vitro culture.embryo culture ͉ organ weight ͉ postnatal defects

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Section: Discussionmentioning

confidence: 99%

Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes, development, and behavior

Fernández‐González

Moreira

Bilbao

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

354

271

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“…Recently, investigators have demonstrated that obesity can also impose structural loads on the airway (5) that elevate pharyngeal collapsibility in the fa/fa rat and that serotonergic mechanisms can offset this mechanical effect (27). We have demonstrated that a similar defect in leptin signaling in obese ob/ob mice accounts for the development of the obesity-hypoventilation syndrome in a murine model (29,38), suggesting that mouse strains may ultimately serve to probe the genetic determinants of sleeprelated breathing disorders. Nevertheless, a mouse model of upper airway function will be required to explore the genetic control of pharyngeal collapsibility.…”

mentioning

confidence: 88%

Neuromechanical control of the isolated upper airway of mice

Liu¹,

Pichard

Schneider³

et al. 2008

Journal of Applied Physiology

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Liu A, Pichard L, Schneider H, Patil SP, Smith PL, Polotsky V, Schwartz AR. Neuromechanical control of the isolated upper airway of mice. J Appl Physiol 105: 1237-1245, 2008. First published July 24, 2008 doi:10.1152/japplphysiol.90461.2008.-We characterized the passive structural and active neuromuscular control of pharyngeal collapsibility in mice and hypothesized that pharyngeal collapsibility, which is elevated by anatomic loads, is reduced by active neuromuscular responses to airflow obstruction. To address this hypothesis, we examined the dynamic control of upper airway function in the isolated upper airway of anesthetized C57BL/6J mice. Pressures were lowered downstream and upstream to the upper airway to induce inspiratory airflow limitation and critical closure of the upper airway, respectively. After hyperventilating the mice to central apnea, we demonstrated a critical closing pressure (Pcrit) of Ϫ6.2 Ϯ 1.1 cmH2O under passive conditions that was unaltered by the state of lung inflation. After a period of central apnea, lower airway occlusion led to progressive increases in phasic genioglossal electromyographic activity (EMGGG), and in maximal inspiratory airflow (V Imax) through the isolated upper airway, particularly as the nasal pressure was lowered toward the passive Pcrit level. Moreover, the active Pcrit fell during inspiration by 8.2 Ϯ 1.4 cmH2O relative to the passive condition (P Ͻ 0.0005). We conclude that upper airway collapsibility (passive Pcrit) in the C57BL/6J mouse is similar to that in the anesthetized canine, feline, and sleeping human upper airway, and that collapsibility falls markedly under active conditions. Active EMGGG and V Imax responses dissociated at higher upstream pressure levels, suggesting a decrease in the mechanical efficiency of upper airway dilators. Our findings in mice imply that anatomic and neuromuscular factors interact dynamically to modulate upper airway function, and provide a novel approach to modeling the impact of genetic and environmental factors in inbred murine strains. obstructive sleep apnea; upper airway collapsibility; critical closing pressure OBSTRUCTIVE SLEEP APNEA is a common disorder with a wide spectrum of neurocognitive, metabolic, and cardiovascular consequences (28,37,39,52,61). Its clinical sequelae stem from frequent nocturnal arousals and/or oxyhemoglobin desaturations, which result from recurrent episodes of upper airway obstruction during sleep (41). Obstruction has been related to elevations in pharyngeal collapsibility during sleep (12,36,47,53), although the mechanism for these elevations is not well understood.Structural alterations and disturbances in neuromuscular control account for elevations in upper airway collapsibility in sleep apnea patients compared with normal controls (36). Boney and soft tissue defects can increase pharyngeal collapsibility by elevating the pressure in tissues around the pharynx (15-19, 59). The impact of structural alterations on upper airway collapsibility may be mitigated by increases in lung volu...

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“…These mice exhibit abnormal patterns of breathing with elevated levels of carbon dioxide. Importantly, the ventilatory response of these mice to carbon dioxide is reduced in both wakefulness and non-REM sleep compared with that of wild-type mouse controls, and is absent during REM sleep [46,47]. In addition, it appears that absence of leptin also produces marked alterations in the mechanical properties of the lung, including reduced total lung capacity and lung compliance [48].…”

Section: Neurohormonal and Neuromodulators Of Breathingmentioning

confidence: 98%

“…Most obese individuals do not hypoventilate, and therefore it has been speculated that these increasing leptin levels may help to maintain alveolar ventilation in the face of the increased ventilatory load caused by obesity [49]. If this compensatory mechanism were lost, for instance with the development of leptin resistance [49,50], then awake hypercapnia could emerge [47,51]. Leptin resistance is recognized in central regulation of appetite and food intake and possibly in other aspects of leptin action [45 ].…”

Section: Neurohormonal and Neuromodulators Of Breathingmentioning

confidence: 99%