Insulin infused into the central nervous system of rats suppresses lipolysis in white adipose tissue, indicating a role of brain insulin in regulating systemic lipid metabolism.We investigated whether central nervous insulin delivery suppresses lipolysis in healthy humans.Placebo-controlled, balanced within-subject comparisons were performed in both a main and an independent corroborative experiment. SETTING/PARTICIPANTS/INTERVENTION: Two groups of healthy volunteers were examined at the German University Clinics of Lübeck and Tübingen, respectively, with molecular analyses taking place at Mt Sinai School of Medicine (New York, New York). The 14 healthy male subjects of the main study and the 22 women and 5 men of the corroborative study each received 160 IU of human insulin intranasally.In the main study, we measured systemic levels of free fatty acids (FFAs), triglycerides, and glycerol and the rate of appearance of deuterated glycerol as an estimate of lipolysis before and after intranasal insulin administration. We also analyzed the expression of key lipolytic enzymes in sc fat biopsies and measured blood glucose and glucoregulatory hormones. In the corroborative study, FFA concentrations were assessed before and after intranasal insulin administration.In the main experiment, intranasal insulin suppressed circulating FFA concentrations and lipolysis (rate of appearance of deuterated glycerol) in the absence of significant changes in circulating insulin levels. Lipolytic protein expression in sc adipose tissue was not affected. The corroborative study confirmed that intranasal insulin lowers systemic FFA concentrations.Our findings indicate that brain insulin controls systemic lipolysis in healthy humans by predominantly acting on non-sc adipose tissue.
Deuterium metabolic imaging (DMI) is an emerging Magnetic Resonance technique providing valuable insight into the dynamics of cellular glucose (Glc) metabolism of the human brain in vivo using deuterium-labeled (
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BackgroundSeveral preclinical and epidemiologic studies have indicated tumour-promoting effects of thyroid hormones (THs). However, very limited knowledge exists on the prognostic impact of thyroid function in metastatic cancer.MethodsWe compiled a discovery cohort of 1692 patients with newly diagnosed brain metastases (BMs) of solid cancers treated at the Medical University of Vienna and an independent validation cohort of 191 patients with newly diagnosed BMs treated at the University Hospital Zurich.ResultsHypothyroidism before diagnosis of cancer was evident in 133 of 1692 (7.9%) patients of the discovery, and in 18 of 191 (9.4%) patients of the validation cohort. In the discovery cohort, hypothyroidism was statistically significantly associated with favourable survival prognosis from diagnosis of cancer (31 vs. 21 months; p = 0.0026) and with survival prognosis from diagnosis of BMs (12 vs. 7 months; p = 0.0079). In multivariate analysis including the diagnosis-specific graded prognostic assessment score, primary tumour type and sex, hypothyroidism was an independent factor associated with survival after diagnosis of BMs (hazard ratio: 0.76; 95% confidence interval [CI]: (0.63; 0.91; p = 0.0034). In the validation cohort, the association of hypothyroidism and favourable survival prognosis from diagnosis of cancer (55 vs. 11 months; p = 0.00058), as well as from diagnosis of BMs (40 vs. 10 months; p = 0.0036) was confirmed.ConclusionPre-existing hypothyroidism was strongly and independently associated with prognosis in patients with newly diagnosed BMs, supporting the evidence from preclinical data that THs may indeed have a tumour-promoting effect. Further investigation of the underlying pathobiological mechanism and potential therapeutic implications are required.
Recombinant human leptin (metreleptin) reduces hepatic lipid content in patients with lipodystrophy and overweight non-alcoholic fatty liver disease patients with relative hypoleptinemia independent of its anorexic action. In rodents, CNS leptin signaling increases very-low density lipoprotein triglyceride (VLDL-TG) secretion and reduces hepatic lipid content via the vagus nerve. In this randomized, placebo-controlled, crossover trial we tested whether a comparable mechanism regulates hepatic lipid metabolism in humans. An acute metreleptin injection stimulated hepatic VLDL-TG secretion and reduced hepatic lipid content in fasted, lean men, but failed to do so in metabolically healthy liver transplant recipients, a model for hepatic denervation. In an independent cohort of lean men, vagal stimulation by modified sham feeding replicated the effects of metreleptin on VLDL-TG secretion. Therefore, we propose that leptin has anti-steatotic properties that are independent of food intake by stimulating hepatic VLDL-TG export via a brain-vagus-liver axis.
