Lower striatal dopamine D2/3 receptor availability in obese compared with non-obese subjects

Background: Obesity is a result of a relative excess in energy intake over energy expenditure. These processes are controlled by genetic, environmental, psychological and biological factors. One of the factors involved in the regulation of food intake and satiety is dopaminergic signalling. A small number of studies have reported that striatal dopamine D-2/D-3 receptor [D2/3R] availability is lower in morbidly obese subjects. Methods: To confirm the role of D2/3R in obesity, we measured striatal D2/3R availability, using [I-123]IBZM SPECT, in 15 obese women and 15 non-obese controls. Results: Striatal D2/3R availability was 23% (p = 0.028) lower in obese compared with non-obese women. Conclusion: This study is an independent replication of the finding that severely obese subjects have lower striatal D2/3R availability. Our findings invigorate the evidence for lower striatal D2/3R availability in obesity and confirm the role of the striatal dopaminergic reward system in obesit

Sexual Dimorphism in Hepatic, Adipose Tissue, and Peripheral Tissue Insulin Sensitivity in Obese Humans

Glucose and lipid metabolism differ between men and women, and women tend to have better whole-body or muscle insulin sensitivity. This may be explained, in part, by differences in sex hormones and adipose tissue distribution. Few studies have investigated gender differences in hepatic, adipose tissue, and whole-body insulin sensitivity between severely obese men and women. In this study, we aimed to determine the differences in glucose metabolism between severely obese men and women using tissue-specific measurements of insulin sensitivity. Insulin sensitivity was compared between age and body mass index (BMI)-matched obese men and women by a two-step euglycemic hyperinsulinemic clamp with infusion of [6,6-H-2(2)]glucose. Basal endogenous glucose production (EGP) and insulin sensitivity of the liver, adipose tissue, and peripheral tissues were assessed. Liver fat content was assessed by proton magnetic resonance spectroscopy in a subset of included subjects. We included 46 obese men and women (age, 48 +/- 2 vs. 46 +/- 2 years, p = 0.591; BMI, 41 +/- 1 vs. 41 +/- 1 kg/m(2), p = 0.832). There was no difference in basal EGP (14.4 +/- 1.0 vs. 15.3 +/- 0.5 mu mol.kg fat-free mass(-1) min(-1), p = 0.410), adipose tissue insulin sensitivity (insulin-mediated suppression of free fatty acids, 71.6 +/- 3.6 vs. 76.1 +/- 2.6%, p = 0.314), or peripheral insulin sensitivity (insulin-stimulated rate of disappearance of glucose, 26.2 +/- 2.1 vs. 22.7 +/- 1.7 mu mol.kg(-1).min(-1), p = 0.211). Obese men were characterized by lower hepatic insulin sensitivity (insulin-mediated suppression of EGP, 61.7 +/- 4.1 vs. 72.8 +/- 2.5% in men vs. women, respectively, p = 0.028). Finally, these observations could not be explained by differences in liver fat content (men vs. women, 16.5 +/- 3.1 vs. 16.0 +/- 2.5%, p = 0.913, n = 27). We conclude that obese men have lower hepatic, but comparable adipose tissue and peripheral tissue, insulin sensitivity compared to similarly obese women. Hepatic insulin resistance may contribute to the higher prevalence of diabetes in obese men. Further insight into the mechanisms underlying this gender difference may reveal novel targets for diabetes prevention and/or therap

RBP4 increases lipolysis in human adipocytes and is associated with increased lipolysis and hepatic insulin resistance in obese women

Retinol-binding protein-4 (RBP4) is elevated in serum and adipose tissue (AT) in obesity-induced insulin resistance and correlates inversely with insulin-stimulated glucose disposal. But its role in insulin-mediated suppression of lipolysis, free fatty acids (FFA), and endogenous glucose production (EGP) in humans is unknown. RBP4 mRNA or protein levels were higher in liver, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in morbidly obese subjects undergoing Roux-en-Y gastric bypass surgery compared to lean controls undergoing elective laparoscopic cholecystectomy. RBP4 mRNA expression in SAT correlated with the expression of several macrophage and other inflammation markers. Serum RBP4 levels correlated inversely with glucose disposal and insulin-mediated suppression of lipolysis, FFA, and EGP. Mechanistically, RBP4 treatment of human adipocytes in vitro directly stimulated basal lipolysis. Treatment of adipocytes with conditioned media from RBP4-activated macrophages markedly increased basal lipolysis and impaired insulin-mediated lipolysis suppression. RBP4 treatment of macrophages increased TNFα production. These data suggest that elevated serum or adipose tissue RBP4 levels in morbidly obese subjects may cause hepatic and systemic insulin resistance by stimulating basal lipolysis and by activating macrophages in adipose tissue, resulting in release of pro-inflammatory cytokines that impair lipolysis suppression. While we have demonstrated this mechanism in human adipocytes in vitro, and correlations from our flux studies in humans strongly support this, further studies are needed to determine whether this mechanism explains RBP4-induced insulin resistance in humans

Blood pressure reduction after gastric bypass surgery is explained by a decrease in cardiac output

Blood pressure (BP) decreases in the first weeks after Roux-and-Y gastric bypass surgery. Yet the pathophysiology of the BP-lowering effects observed after gastric bypass surgery is incompletely understood. We evaluated BP, systemic hemodynamics, and baroreflex sensitivity in 15 obese women[mean age 42 +/- 7 standard deviation (SD) yr, body mass index 45 +/- 6 kg/m2] 2 wk before and 6 wk following Roux-and-Y gastric bypass surgery. Six weeks after gastric bypass surgery, mean body weight decreased by 13 +/- 5 kg (10%, P < 0.001). Office BP decreased from 137 +/- 10/86 +/- 6 to 128 +/- 12/81 +/- 9 mmHg (P < 0.001, P < 0.01), while daytime ambulatory BP decreased from 128 +/- 14/80 +/- 9 to 114 +/- 10/73 +/- 6 mmHg (P = 0.01, P = 0.05), whereas nighttime BP decreased from 111 +/- 13/66 +/- 7 to 102 +/- 9/62 +/- 7 mmHg (P = 0.04, P < 0.01). The decrease in BP was associated with a 1.6 +/- 1.2 l/min (20%, P < 0.01) decrease in cardiac output (CO), while systemic vascular resistance increased (153 +/- 189 dyn s cm-5, 15%, P < 0.01). The maximal ascending slope in systolic blood pressure decreased (192 mmHg/s, 19%, P = 0.01), suggesting a reduction in left ventricular contractility. Baroreflex sensitivity increased from 9.0 [6.4-14.3] to 13.8 [8.5-19.0] ms/mmHg (median [interquartile range]; P < 0.01) and was inversely correlated with the reductions in heart rate (R = -0.64, P = 0.02) and CO (R = -0.61, P = 0.03). In contrast, changes in body weight were not correlated with changes in either BP or CO. The BP reduction following Roux-and-Y gastric bypass surgery is correlated with a decrease in CO independent of changes in body weight. The contribution of heart rate to the reduction in CO together with enhanced baroreflex sensitivity suggests a shift toward increased parasympathetic cardiovascular control. The reason for the decrease in blood pressure (BP) in the first weeks after gastric bypass surgery remains to be elucidated. We show that the reduction in BP following surgery is caused by a decrease in cardiac output. In addition, the maximal ascending slope in systolic blood pressure decreased suggesting a reduction in left ventricular contractility and cardiac workload. These findings help to understand the physiological changes following gastric bypass surgery and are relevant in light of the increased risk of heart failure in these patient

Adipositas, Kognition und Entscheidungsverhalten

Entscheidungen zu fällen, ist ein integraler Bestandteil des täglichen Lebens. Im Kontext von Adipositas sind Entscheidungen von besonderem Interesse, die das Essverhalten und die physische Aktivität beeinflussen. Wie wir uns letztendlich entscheiden, hängt von einer Fülle von Faktoren ab. Diese sind unter anderem der erwartete Belohnungswert, der Aufwand, den es aufzubringen gilt, ob wir alle Alternativen kennen und schon Erfahrungen damit gesammelt haben, aber auch welche ausdrücklichen Ziele wir uns gesteckt haben. Zusätzlich bestimmt unser Gehirn, wie wahrscheinlich es ist, dass wir uns für die eine oder andere Alternative entscheiden. Warum aber fällt es Menschen mit Adipositas so schwer, ihr Verhalten so zu steuern, dass es mit ihren ausdrücklich formulierten Zielen übereinstimmt? Könnte es sein, dass Gehirnsysteme, welche die Entscheidungsfindung stützen, als Folge von Adipositas verändert sind? In diesem Kapitel sollen die Eigenheiten von Kognition, Entscheidungsfindung und Gehirnfunktion bei Adipositas hervorgehoben werden, die auf tiefgreifende Unterschiede zwischen Personen mit und ohne Adipositas in Gehirnsystemen hinweisen, die die Verhaltenskontrolle steuern. Unterschiede in diesen Hirnsystemen könnten eine mechanistische Erklärung dafür liefern, dass Personen mit Adipositas Schwierigkeiten gegenüber stehen, wenn sie versuchen, ihr Verhalten zu ändern