The prevalence of obesity is increasing dramatically in western society, especially in the U.S. where 22% of the population have a body mass index greater than 30 kg/m2. As weight is gained, individuals can develop elevated, resting levels of PaCO2 and depressed hypercapnic ventilatory responses (Obesity Hypoventilation Syndrome; OHS). The mechanisms that link obesity and respiratory depression are unclear. The premise of this proposal is that the recently cloned metabolic hormone, leptin, can prevent respiratory depression in obesity. Our findings indicate that obese ob/ob mice, which lack circulating leptin, exhibit the major clinical features of OHS, and that leptin replacement reverses respiratory depression independent of weight. The current application is designed to explore influences of leptin on ventilatory control, and the pathways and factors which modulate its effect. Various transgenic mice and novel techniques are employed to measure ventilation, sleep wake/state and arterial blood gases in chronically instrumented mice. Insights gained from murine experiments will be applied in humans to define the relationship between leptin and ventilation in obesity.
Specific Aim l, examines whether leptin can increase the gain of central chemoreceptors, and whether an acute 10% reduction in body fat in obese mice affects ventilatory control.
Specific Aim 2 examines whether leptin acts through hypothalamic and peripheral chemoreceptor pathways to alter respiratory control.
Specific Aim 3, examines whether leptin is upregulated as a compensatory response to chronic hypoxia.
In Specific Aim 4, the mechanistic animal studies will be extended to determine how leptin levels in the CNS relate to PaCO2 in severely obese humans. Finally, the role of gender and sleep/wake state will be explored across Specific Aims 1-4. These studies will enhance understanding of the pathogenesis of respiratory failure in obesity, provide insight into the role of leptin in patients with ventilatory insufficiency of other causes, and offer the possibility of specific therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063767-03
Application #
6537707
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Twery, Michael
Project Start
2000-07-10
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$286,125
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Lakshmipathi, Jayalakshmi; Alvarez-Perez, Juan Carlos; Rosselot, Carolina et al. (2016) PKC? Is Essential for Pancreatic ?-Cell Replication During Insulin Resistance by Regulating mTOR and Cyclin-D2. Diabetes 65:1283-96
Lee, Euhan J; Alonso, Laura C; Stefanovski, Darko et al. (2013) Time-dependent changes in glucose and insulin regulation during intermittent hypoxia and continuous hypoxia. Eur J Appl Physiol 113:467-78
Alonso, Laura C; Watanabe, Yoshio; Stefanovski, Darko et al. (2012) Simultaneous measurement of insulin sensitivity, insulin secretion, and the disposition index in conscious unhandled mice. Obesity (Silver Spring) 20:1403-12
Pascoe, Jordan; Hollern, Douglas; Stamateris, Rachel et al. (2012) Free fatty acids block glucose-induced ?-cell proliferation in mice by inducing cell cycle inhibitors p16 and p18. Diabetes 61:632-41
Dempsey, Jerome A; Veasey, Sigrid C; Morgan, Barbara J et al. (2010) Pathophysiology of sleep apnea. Physiol Rev 90:47-112
Lee, Euhan J; Woodske, Matthew E; Zou, Baobo et al. (2009) Dynamic arterial blood gas analysis in conscious, unrestrained C57BL/6J mice during exposure to intermittent hypoxia. J Appl Physiol (1985) 107:290-4
Sanders, Mark H; Montserrat, Josep M; Farre, Ramon et al. (2008) Positive pressure therapy: a perspective on evidence-based outcomes and methods of application. Proc Am Thorac Soc 5:161-72
Yokoe, Takuya; Alonso, Laura C; Romano, Lia C et al. (2008) Intermittent hypoxia reverses the diurnal glucose rhythm and causes pancreatic beta-cell replication in mice. J Physiol 586:899-911
Iiyori, Nao; Alonso, Laura C; Li, Jianguo et al. (2007) Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am J Respir Crit Care Med 175:851-7
Polotsky, Vsevolod Y; Rubin, Arnon E; Balbir, Alex et al. (2006) Intermittent hypoxia causes REM sleep deficits and decreases EEG delta power in NREM sleep in the C57BL/6J mouse. Sleep Med 7:7-16

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