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Gastric emptying and sodium intake by dehydrated rats after serotonergic blockade in the lateral parabrachial nucleus
642
Abstracts / Appetite 54 (2010) 631–683
Gastric emptying and sodium intake by dehydrated rats after serotonergic blockade in the lateral parabrachial nucleus R.B. DAVID ∗ , C.F. RONCARI, J.V. MENANI, L.A. DE LUCA JR. Department Physiology & Pathology, School of Dentistry, São Paulo State University, Araraquara, Brazil Serotonergic blockade with methysergide (METHY) in the lateral parabrachial nucleus (LPBN) enhances hypertonic NaCl intake in dehydrated rats. This blockade might increase gastric emptying rate of hypertonic NaCl, thereby reducing inhibitory signals for NaCl intake. Water and 0.3 M NaCl intake was tested in rats treated with bilateral injections of METHY (4 g/0.2 l) or vehicle (VEH) into the LPBN combined with previous (45 min before) sc injection of furosemide (FURO, 10 mg/rat) or iv infusion of 2 M NaCl (1.5 ml/10 min). METHY induced 0.3 M NaCl intake in FURO-treated rats (14.6 ± 1.6 ml/2 h; VEH: 4.0 ± 0.6 ml/2 h; n = 24) or hyperosmotic rats (14.1 ± 3.3 ml/2 h; VEH: 1.7 ± 0.5 ml/2 h; n = 11). Five days later, rats were dehydrated again by sc FURO plus overnight sodium restriction (late-hypovolemia) or iv NaCl 2 M. Then, 15 min after METHY or VEH into the LPBN, they received a fixed amount (3 ml) of 0.3 M NaCl either to drink (late-hypovolemic rats) or by gavage (cell-dehydrated rats). The stomachs were removed 10 min after the initial access to 0.3 M NaCl for determination of their total liquid content. METHY did not alter stomach liquid content in celldehydrated (2.9 ± 0.2 g, n = 6; VEH: 3.2 ± 0.2 g, n = 5), but reduced it in sodium depleted rats (2.1 ± 0.1 g, n = 6; vs. VEH: 2.5±0.3 g, n = 7). The results suggest that alterations in gastric empting of hypertonic NaCl are not essential for the effect of METHY on 0.3 M NaCl intake. Support: CNPq, FAPESP. doi:10.1016/j.appet.2010.04.053
SeXX and adipose tissue K. DAVIS ∗ , L. HAHNER, L. GENT, Z. WANG, D. CLEGG University of Texas Southwestern Medical, Dallas, TX, USA Disruption of estrogen (E2) signaling by estrogen receptor (ER)␣ ablation yields an obese, glucose intolerant phenotype. These findings support a role for E2 and ER␣ in preventing obesity; however, the molecular mechanisms and tissue specific sites conferring ER␣ activity are unknown. ER␣ is expressed in multiple tissues, and here we have developed a novel mouse model with which we can directly study the effects of ER␣ in adipocytes. To this end we have employed the ER␣lox/lox mouse crossed to a mouse that expresses CRE recombinase under the control of the adiponectin promoter. Adiponectin expression is highly restricted to adipocytes and is not present in macrophages or in other components of the stromal vascular fraction of adipose tissue. Preliminary analyses of these mice demonstrate that female ER␣lox/lox /Adipo-CRE mice differ in body weight but not food intake when compared to their ER␣lox/lox littermate controls. However, the ER␣lox/lox /Adipo-CRE mice show an increased triglyceride deposition in their visceral adipose depots and enlarged visceral adipocytes. Moreover, both male and female ER␣lox/lox /Adipo-CRE mice have impaired glucose tolerance when compared to ER␣lox/lox littermates. Additionally, male ER␣lox/lox /Adipo-CRE mice have decreased pyruvate tolerance, suggesting that this glucose intolerance is the result of liver insulin resistance. In conclusion, our data demonstrate that adipocyte ER␣ is crucial in mediating adipocyte and systemic metabolic homeostasis. doi:10.1016/j.appet.2010.04.054
Optogenetic control of arousal and brain reward LUIS DE LECEA Stanford University, Palo Alto, CA, USA The hypothalamus is a federation of nuclei with diverse functions in the regulation of homeostasis and behavior. The complex and heterogeneous nature of hypothalamic nuclei makes it difficult to assign causal relationships between activity of defined cell groups and complex behavior. We have recently targeted the light activated cation channel, channel rhodopsin 2 (ChR2) to different hypothalamic cell groups that promote arousal. We have demonstrated that optogenetic stimulation of neurons producing hypocretins (also known as orexins) increases the probability of sleep to wake transitions. However, mild homeostatic sleep pressure prevents these optogenetic-induced transitions. We have also demonstrated that low frequency activity noradrenergic neurons in the locus coeruleus, which receive direct synaptic input from hypocretin neurons, is sufficient to drive sleep to wake transitions. In sum, optogenetics can establish causal relationships between the activity of genetically defined cell groups and sleep-to-wake transitions with an unprecedented millisecond temporal resolution. doi:10.1016/j.appet.2010.04.055
Programmed impairment of hypothalamic neural stem cell proliferation and differentiation. Mechanism of adult obesity in low birth weight (LBW) offspring M. DESAI ∗ , T. LI, M.G. ROSS Dept of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Torrance, CA, USA LBW offspring exhibit reduced hypothalamic neural satiety pathways and dysregulated signaling leading to programmed hyperphagia and adult obesity. Hypothalamic appetite circuits develop during early life, under the influence of neurotrophic hormones (leptin, insulin). Notably, LBW newborns have reduced plasma leptin and insulin levels. As neurons and glia arise from neuronal precursor cells (NPC), we postulated that a programmed impairment of NSCs may contribute to reduced hypothalamic neural pathway development in LBW offspring. Control dams received ad libitum food, whereas study dams were 50% food-restricted from pregnancy day 10–21 to produce LBW newborns. At day 1 of age, hypothalamic NPCs were cultured as neurospheres (NS) and treated with leptin (10, 20, 40 ng/ml) or insulin (10, 20, 40 g/ml). Cell proliferation and differentiation into neurons or astrocytes was analyzed. LBW NS had markedly reduced basal (50–60%) and leptin/insulin stimulated proliferation as compared to Controls. Further, LBW NS had reduced basal differentiation to both neuronal (22%) and astrocyte (42%) cell lines. In response to leptin, LBW NS exhibited significantly reduced differentiation to both neurons (34%) and astrocytes (29%). In contrast to leptin, insulin induced NS differentiation only to neurons, with a marked impairment evident in LBW as compared to Controls. Thus, programmed dysfunctional hypothalamic NPCs likely contribute to reduced anorexigenic neural pathways in LBW offspring, and to the resulting hyperphagia and obesity. doi:10.1016/j.appet.2010.04.056
Abstracts / Appetite 54 (2010) 631–683
Gastric emptying and sodium intake by dehydrated rats after serotonergic blockade in the lateral parabrachial nucleus R.B. DAVID ∗ , C.F. RONCARI, J.V. MENANI, L.A. DE LUCA JR. Department Physiology & Pathology, School of Dentistry, São Paulo State University, Araraquara, Brazil Serotonergic blockade with methysergide (METHY) in the lateral parabrachial nucleus (LPBN) enhances hypertonic NaCl intake in dehydrated rats. This blockade might increase gastric emptying rate of hypertonic NaCl, thereby reducing inhibitory signals for NaCl intake. Water and 0.3 M NaCl intake was tested in rats treated with bilateral injections of METHY (4 g/0.2 l) or vehicle (VEH) into the LPBN combined with previous (45 min before) sc injection of furosemide (FURO, 10 mg/rat) or iv infusion of 2 M NaCl (1.5 ml/10 min). METHY induced 0.3 M NaCl intake in FURO-treated rats (14.6 ± 1.6 ml/2 h; VEH: 4.0 ± 0.6 ml/2 h; n = 24) or hyperosmotic rats (14.1 ± 3.3 ml/2 h; VEH: 1.7 ± 0.5 ml/2 h; n = 11). Five days later, rats were dehydrated again by sc FURO plus overnight sodium restriction (late-hypovolemia) or iv NaCl 2 M. Then, 15 min after METHY or VEH into the LPBN, they received a fixed amount (3 ml) of 0.3 M NaCl either to drink (late-hypovolemic rats) or by gavage (cell-dehydrated rats). The stomachs were removed 10 min after the initial access to 0.3 M NaCl for determination of their total liquid content. METHY did not alter stomach liquid content in celldehydrated (2.9 ± 0.2 g, n = 6; VEH: 3.2 ± 0.2 g, n = 5), but reduced it in sodium depleted rats (2.1 ± 0.1 g, n = 6; vs. VEH: 2.5±0.3 g, n = 7). The results suggest that alterations in gastric empting of hypertonic NaCl are not essential for the effect of METHY on 0.3 M NaCl intake. Support: CNPq, FAPESP. doi:10.1016/j.appet.2010.04.053
SeXX and adipose tissue K. DAVIS ∗ , L. HAHNER, L. GENT, Z. WANG, D. CLEGG University of Texas Southwestern Medical, Dallas, TX, USA Disruption of estrogen (E2) signaling by estrogen receptor (ER)␣ ablation yields an obese, glucose intolerant phenotype. These findings support a role for E2 and ER␣ in preventing obesity; however, the molecular mechanisms and tissue specific sites conferring ER␣ activity are unknown. ER␣ is expressed in multiple tissues, and here we have developed a novel mouse model with which we can directly study the effects of ER␣ in adipocytes. To this end we have employed the ER␣lox/lox mouse crossed to a mouse that expresses CRE recombinase under the control of the adiponectin promoter. Adiponectin expression is highly restricted to adipocytes and is not present in macrophages or in other components of the stromal vascular fraction of adipose tissue. Preliminary analyses of these mice demonstrate that female ER␣lox/lox /Adipo-CRE mice differ in body weight but not food intake when compared to their ER␣lox/lox littermate controls. However, the ER␣lox/lox /Adipo-CRE mice show an increased triglyceride deposition in their visceral adipose depots and enlarged visceral adipocytes. Moreover, both male and female ER␣lox/lox /Adipo-CRE mice have impaired glucose tolerance when compared to ER␣lox/lox littermates. Additionally, male ER␣lox/lox /Adipo-CRE mice have decreased pyruvate tolerance, suggesting that this glucose intolerance is the result of liver insulin resistance. In conclusion, our data demonstrate that adipocyte ER␣ is crucial in mediating adipocyte and systemic metabolic homeostasis. doi:10.1016/j.appet.2010.04.054
Optogenetic control of arousal and brain reward LUIS DE LECEA Stanford University, Palo Alto, CA, USA The hypothalamus is a federation of nuclei with diverse functions in the regulation of homeostasis and behavior. The complex and heterogeneous nature of hypothalamic nuclei makes it difficult to assign causal relationships between activity of defined cell groups and complex behavior. We have recently targeted the light activated cation channel, channel rhodopsin 2 (ChR2) to different hypothalamic cell groups that promote arousal. We have demonstrated that optogenetic stimulation of neurons producing hypocretins (also known as orexins) increases the probability of sleep to wake transitions. However, mild homeostatic sleep pressure prevents these optogenetic-induced transitions. We have also demonstrated that low frequency activity noradrenergic neurons in the locus coeruleus, which receive direct synaptic input from hypocretin neurons, is sufficient to drive sleep to wake transitions. In sum, optogenetics can establish causal relationships between the activity of genetically defined cell groups and sleep-to-wake transitions with an unprecedented millisecond temporal resolution. doi:10.1016/j.appet.2010.04.055
Programmed impairment of hypothalamic neural stem cell proliferation and differentiation. Mechanism of adult obesity in low birth weight (LBW) offspring M. DESAI ∗ , T. LI, M.G. ROSS Dept of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Torrance, CA, USA LBW offspring exhibit reduced hypothalamic neural satiety pathways and dysregulated signaling leading to programmed hyperphagia and adult obesity. Hypothalamic appetite circuits develop during early life, under the influence of neurotrophic hormones (leptin, insulin). Notably, LBW newborns have reduced plasma leptin and insulin levels. As neurons and glia arise from neuronal precursor cells (NPC), we postulated that a programmed impairment of NSCs may contribute to reduced hypothalamic neural pathway development in LBW offspring. Control dams received ad libitum food, whereas study dams were 50% food-restricted from pregnancy day 10–21 to produce LBW newborns. At day 1 of age, hypothalamic NPCs were cultured as neurospheres (NS) and treated with leptin (10, 20, 40 ng/ml) or insulin (10, 20, 40 g/ml). Cell proliferation and differentiation into neurons or astrocytes was analyzed. LBW NS had markedly reduced basal (50–60%) and leptin/insulin stimulated proliferation as compared to Controls. Further, LBW NS had reduced basal differentiation to both neuronal (22%) and astrocyte (42%) cell lines. In response to leptin, LBW NS exhibited significantly reduced differentiation to both neurons (34%) and astrocytes (29%). In contrast to leptin, insulin induced NS differentiation only to neurons, with a marked impairment evident in LBW as compared to Controls. Thus, programmed dysfunctional hypothalamic NPCs likely contribute to reduced anorexigenic neural pathways in LBW offspring, and to the resulting hyperphagia and obesity. doi:10.1016/j.appet.2010.04.056