Linkage of serum leptin levels in families with sleep apnea

Abstract

OBJECTIVE:To identify regions on the genome linked to plasma leptin levels. DESIGN: Full genome scan with 402 microsatellite markers, spaced B10 cM apart. Data were analyzed using the HasemanElston regression linkage analysis. SUBJECTS: A total of 160 sibling pairs from 59 predominantly African American, obese families recruited to participate in a genetic-epidemiological study of obstructive sleep apnea. MEASUREMENTS: Serum leptin levels adjusted for age, sex, race and body mass index (BMI). RESULTS: Suggestive linkage peaks were observed on chromosomes 2 (P ¼ 0.00170; marker D2S1384), 3 (P ¼ 0.00007; marker D3S3034), 4 (P ¼ 0.00020; marker D4S1652) and 21 (P ¼ 0.00053; marker D21s1411). CONCLUSION: The peak on chromosome 3 is near the gene for glycogensynthase kinase 2 beta, an important factor in glucose homeostasis. Linkage was generally stronger after BMI adjustment, suggesting the potential influence of a number of metabolic pathways on leptin levels other than those that directly determine obesity levels. The evidence of linkage for leptin levels is consistent with prior linkage analyses for cholesterol, hypertension and other metabolic phenotypes.

Leptin signaling in the nucleus of the solitary tract alters the cardiovascular responses to activation of the chemoreceptor reflex

“…Additionally, leptin not only potentiated the cardiovascular responses elicited by L-Glu injections at the same NTS site, but also potentiated the cardiovascular responses resulting from the activation of peripheral chemoreceptors. These novel findings of leptin's actions on the reflex cardiovascular responses evoked by activation of the chemoreceptor reflex have considerable implications in the understanding of the contribution of leptin to autonomic changes during conditions of systemic hypoxia, especially as during CIH, leptin levels have been reported to be elevated (39,46,64), suggesting that these elevated levels of leptin may contribute to the resulting hypertension. The finding in this study that leptin exerts an effect on cardiovascular regulatory systems in NTS independent of the hypothalamus is consistent with a number of recent studies showing that leptin can have a direct effect on brain stem neuronal systems.…”

“…The resulting hypertension is thought to be the result of activation of peripheral chemoreceptors (25). Interestingly, individuals suffering from CIH have also been shown to have high circulating levels of leptin independent of their body weight (39,46,60,64). Thus, it is not unreasonable to suggest that the higher circulating levels of leptin may contribute to the hypertension in these patients by altering the sensitivity of the chemoreceptor reflex at the level of NTS.…”

“…Considerable data exist, suggesting that CIH may contribute to increased arterial pressure (AP) through the activation of the chemoreceptor reflex by the resulting systemic hypoxia (2,3,6,7,25,59). Leptin, a circulating adipocytokine produced by the adipose tissue, has been shown to be elevated during CIH (39,46,60,64), suggesting a possible link between leptin and the autonomic responses elicited by the chemoreceptor reflex. In support of this suggestion, a recent study has found that leptin injections into the nucleus of the solitary tract (NTS) alter the ventilatory response during activation of the Hering-Breuer reflex (43,44).…”

Systemic administration of leptin potentiates the response of neurons in the nucleus of the solitary tract to chemoreceptor activation in the rat

“…Additionally, systemic injections of leptin potentiate the responses of these NTS neurons to activation of the peripheral chemoreceptor. These observations may be of some clinical importance as chronic intermittent hypoxia is known not only to activate peripheral chemoreceptors as a result of the decreased arterial partial pressure of oxygen but also to increase plasma levels of leptin in both animal models of the disease (Messenger et al, 2012) and in patients independent of body weight (Scha¨fer et al, 2002;Harsch et al, 2003;Patel et al, 2004;Larkin et al, 2005). Patients that suffer from chronic intermittent hypoxia also have elevated arterial pressure and increased sympathetic nerve activity as a result of the reflex activation of peripheral chemoreceptors (Dempsey et al, 2010).…”

“…Taken together, these data suggest the possibility that a component of the sympathoexcitatory responses mediated by leptin may involve activation of NTS neurons that receive chemoreceptor inputs (Chitravanshi and Sapru, 1995;Koshiya and Guyenet, 1996) and excite pre-sympathetic neurons in the RVLM (Ciriello et al, 1986;Colombari et al, 1996;Koshiya and Guyenet, 1996;Sapru, 1996;Cruz et al, 2008). Furthermore, these data can be interpreted to suggest that obese individuals with high circulating levels of leptin (hall et al, 2001;Harsch et al, 2003), and that suffering from intermittent hypoxia (Baguet et al, 2009;Dempsey et al, 2010), may be susceptible to an exacerbation of the chemoreceptor reflex resulting from leptin release (Messenger et al, 2012) which may contribute to obesity-induced hypertension (Scha¨fer et al, 2002;Patel et al, 2004;Larkin et al, 2005). This latter suggestion is supported by the recent finding that leptin injections directly into the NTS not only elicit increases in arterial pressure, heart rate and renal sympathetic nerve activity (Arnold et al, 2009;Mark et al, 2009;Ciriello and Moreau, 2012) but also potentiates the cardiovascular responses to activation of the carotid chemoreceptor reflex , while inhibiting the cardiac vagal component of the baroreceptor reflex (Ciriello, 2006;Arnold et al, 2009).…”