Time-dependent PPARγ Modulation of HIF-1α Signaling in Hypoxic Pulmonary Artery Smooth Muscle Cells.

BACKGROUND: Pathogenesis of pulmonary hypertension is complex and involves activation of the transcription factor, hypoxia-inducible factor-1 (HIF-1) that shifts cellular metabolism from aerobic respiration to glycolysis, in part, by increasing the expression of its downstream target pyruvate dehydrogenase kinase-1 (PDK-1), thereby promoting a proliferative, apoptosis-resistant phenotype in pulmonary vascular cells. Activation of the nuclear hormone transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), attenuates pulmonary hypertension and pulmonary artery smooth muscle cell (PASMC) proliferation. In the current study, we determined whether PPARγ inhibits HIF-1α and PDK-1 expression in human PASMCs. METHODS: HPASMCs were exposed to normoxia (21% O2) or hypoxia (1% O2) for 2-72 hours ± treatment with the PPARγ-ligand, rosiglitazone (RSG, 10µM). RESULTS: Compared to normoxia, HIF-1α mRNA levels were elevated in HPASMC at 2 hours hypoxia and reduced to baseline levels by 24-72 hours. HIF-1α protein levels increased following 4 and 8 hours of hypoxia and returned to baseline levels by 24 and 72 hours. PDK-1 protein levels increased following 24 hours hypoxia and remained elevated by 72 hours. RSG treatment at the onset of hypoxia attenuated HIF-1α protein and PDK-1 mRNA and protein levels at 4, 8 and 24 hours of hypoxia, respectively. However, RSG treatment during final 24 hours of 72-hour hypoxia, an intervention that inhibits HPASMC proliferation, failed to prevent hypoxia-induced PDK-1 expression. CONCLUSION: Hypoxia causes transient activation of HPASMC HIF-1α that is attenuated by RSG treatment initiated at hypoxia onset. These findings provide novel evidence that PPARγ modulates fundamental and acute cellular responses to hypoxia through both HIF-1-dependent and HIF-1-independent mechanisms.

Leptin levels are associated with decreased depressive symptoms in women across the weight spectrum, independent of body fat.

OBJECTIVE: Leptin is anorexigenic, and levels are markedly decreased in women with low body weight and high in women with obesity. Ghrelin opposes leptin effects on appetite and is negatively associated with body mass index. These appetite-regulating hormones may have opposing effects on mood and stress pathways. Women with anorexia nervosa (AN), hypothalamic amenorrhoea (HA) and obesity are at increased risk of depression and anxiety. It is unknown whether dysregulation of leptin or ghrelin contributes to the development of depression and/or anxiety in these disorders. We investigated the relationship between leptin and ghrelin levels and symptoms of depression, anxiety and perceived stress in women across the weight spectrum. DESIGN: Cross-sectional. PATIENTS: 64 women: 15 with AN, 12 normal-weight with HA, 17 overweight or obese (OB) and 20 normal-weight in good health (HC). MEASUREMENTS: Fasting serum leptin and plasma ghrelin levels were measured. Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A) and the Perceived Stress Scale were administered. RESULTS: Leptin levels were inversely associated with HAM-D, HAM-A and Perceived Stress scores. The negative relationships between leptin and severity of symptoms of both depression and anxiety remained significant after controlling for body fat or weight. There was no relationship between ghrelin and symptoms of depression or anxiety. Although ghrelin levels were positively associated with the degree of perceived stress, this relationship was not significant after controlling for body fat or weight. CONCLUSIONS: Leptin may mediate depressive symptoms across the weight spectrum. Further investigation of the role of leptin in modulating mood will be important.

Decreased nocturnal oxytocin levels in anorexia nervosa are associated with low bone mineral density and fat mass.

OBJECTIVE: Anorexia nervosa is characterized by self-induced starvation and associated with severe bone and fat loss. Oxytocin is a peptide hormone involved in appetite and energy homeostasis. Recent data show that oxytocin has an anabolic effect on bone and stimulates osteoblast function. There is limited information about oxytocin levels or their relationship to decreased bone mineral density in anorexia nervosa. Our objective was to investigate the relationship between oxytocin levels, bone mineral density, and body composition in women with anorexia nervosa. METHOD: We studied 36 women, mean ± SEM age 27.6 ± 1.3 years: 17 with DSM-IV anorexia nervosa and 19 healthy controls in a cross-sectional study. Oxytocin levels were determined from pooled serum samples obtained every 20 minutes from 8 pm to 8 am during an inpatient overnight visit. Fasting leptin levels were measured. Bone mineral density at the anterior-posterior and lateral spine and hip and body composition were assessed by dual energy x-ray absorptiometry. The study was conducted from September 2004 to June 2008. RESULTS: Subjects with anorexia nervosa versus healthy controls had lower mean ± SEM oxytocin levels (14.3 ± 1.5 vs 31.8 ± 5.1 pg/mL, P = .003), leptin levels (2.7 ± 0.5 vs 11.4 ± 1.1 ng/mL, P < .0001), bone mineral density (anterior-posterior spine: 0.83 ± 0.02 vs 1.04 ± 0.03; lateral spine: 0.63 ± 0.02 vs 0.81 ± 0.02; total hip: 0.79 ± 0.03 vs 0.97 ± 0.03 g/cm², P < .0001), and fat mass (8.8 ± 0.6 vs 19.7 ± 0.9 kg, P < .0001). Oxytocin levels were associated with bone mineral density at the anterior-posterior (r = 0.40, P = .02) and lateral (r = 0.36, P = .04) spine, fat mass (r = 0.42, P = .01), and leptin levels (r = 0.55, P = .001). CONCLUSIONS: Overnight secretion of oxytocin in women with anorexia nervosa is decreased compared with healthy women. Low oxytocin levels are associated with decreased bone mineral density and body fat and may contribute to anorexia nervosa-induced bone loss.