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Insulin infused into the central nervous Mainz casual sex 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 Ladies looking sex Dayton Montana 59914 main and an independent corroborative experiment. The 14 healthy male subjects of the main study and the 22 women and 5 men of the corroborative study each received IU of human insulin intranasally. In the main study, we measured systemic levels of free fatty acids FFAstriglycerides, 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 ificant 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.
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Insulin controls white adipose tissue WAT metabolism by suppressing lipolysis and inducing lipogenesis, effects that have long been considered to be mediated exclusively by insulin receptors expressed on adipocytes 1. However, mice that lack the insulin receptor in all peripheral tissues including WAT display only a mild reduction of fat mass 2. In contrast, deletion of both peripheral and central insulin receptors in mice le to severe lipodystrophy 3. We Housewives personals in Villa park CA demonstrated that insulin infused into the hypothalamus of rats rapidly suppresses lipolysis by dampening sympathetic nervous system SNS outflow to visceral WAT 4.
In these studies we also found that WAT de novo lipogenesis is enhanced by brain insulin and is reduced after the loss of central insulin receptors. Thus, these findings in rodents Housewives looking sex tonight Briggs Texas that after uptake into the brain, insulin regulates WAT metabolism by suppressing lipolysis and inducing lipogenesis, both core metabolic functions of insulin 5.
Whether brain insulin serves a similar function in higher mammals is unclear, and there has been no study to examine the impact of brain insulin on lipolysis in humans. Intranasal administration delivers insulin via trigeminal and olfactory nerve fibers to the brain without relevant systemic absorption Lady looking sex Assawoman and has been widely used to investigate central nervous insulin effects 7 — 9.
To study the role of brain insulin in the regulation of lipolysis in adipose tissue, we administered insulin intranasally to lean healthy volunteers and assessed the rate of appearance of deuterated glycerol Ra glycerol as an estimate of systemic lipolysis, as well as circulating fatty acid levels. Two placebo-controlled, balanced within-subject studies main and corroborative conforming to the Declaration of Helsinki and approved by the local ethics committees were conducted in healthy subjects after obtaining informed consent.
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A microdialysis catheter was placed in abdominal sc adipose tissue Blood was sampled every 15—30 minutes. After calibration, microdialysis measurements of glycerol were Naked women from Jonesboro ms. At amsubjects received IU of insulin 1.
Throughout the experiments, participants were monitored as ly described 10 De of the main study and key .
A, At aman infusion of d-[1,1,2,3,3—2H5]glycerol and microdialysis started. Baseline blood sampling took place at amamand am for blood glucose, C-peptide, and insulin, and at am and am for all other blood parameters along with one baseline collection of sc adipose tissue via biopsy at am. Mean baseline values of both conditions are averaged to a common baseline.
Activation state of Hsl as assessed by Western blot analyses using phospho-specific antibodies detecting the activating phosphorylation sites Ser Wife want casual sex Hesperia and Ser H in sc adipose tissue biopsied 30 minutes before baseline and minutes after intranasal administration of placebo white bars and insulin black bars is also shown.
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J, Corroborative study. Plasma concentrations of FFAs left and insulin right expressed as AUC 0—60min after intranasal administration of placebo white bars and IU insulin black barsrespectively, adjusted for sex.
Isotope enrichment was determined by gas chromatography-mass spectrometry. Some of these samples were derived from ly published experiments Baseline adjustment was achieved by individually subtracting averaged baseline values from posttreatment values.
Analyses relied on an ANOVA with the repeated-measure factors treatment and time, and Greenhouse-Geisser correction of degrees of freedom. Two-sided pairwise t tests were used for comparisons of areas under the curve AUCs calculated according to the trapezoidal rule.
Four subjects of the main study were excluded from analysis of sc adipose tissue glycerol Housewives looking casual sex PA Finleyville 15332 two subjects from the analysis of Ra glycerol due to technical failures. Exploratory biopsy analyses were restricted to seven subjects.
Likewise, the activation state of the key lipolytic enzyme hormone-sensitive lipase Hslas assessed by Western blot analyses using phospho-specific antibodies against the activating phosphorylation sites Ser and Ser, was unaltered by intranasal insulin Figure 1G and H. The suppressive effect of intranasal insulin on circulating FFA concentrations was confirmed in our independent corroborative study in men and women Figure 1 J. AUC 0— min values were calculated for serum and plasma concentrations, respectively, assessed after intranasal administration of insulin IU and placebo.
AUC values derived from individually baseline-adjusted data were set to a common baseline averaged across conditions. We demonstrate in humans that administering insulin intranasally to raise central nervous Chat in Lakewood Colorado port CNS insulin levels suppresses systemic lipolysis as assessed by Ra glycerol and circulating FFA measurements.
These extend to humans findings in rodents 4 that established brain insulin as a regulator of WAT lipolysis. Systemic concentrations of insulin, C-peptide, glucose, and Sweet wives want hot sex Topeka Kansas were not affected by intranasal insulin, indicating that its effect on lipolysis was not mediated through changes in circulating insulin or glucose, and suggesting that the regulation of lipolysis is more sensitive to changes in CNS insulin aling than systemic glucose homeostasis.
Although we cannot completely rule out that a small amount of intranasal insulin may enter the bloodstream via the nasal mucosa, in both of our cohorts, the suppression of lipolysis was statistically independent from any changes in serum insulin levels, supporting the notion that the effect of intranasal insulin was predominantly conveyed via central nervous pathways. In line with this conclusion, we found no ificant differences between conditions in circulating fT3, TSH, and stress hormones, which are known to affect systemic lipolysis Also, no effect of intranasal insulin on leptin, an adipokine regulating Wife looking hot sex WI Custer 54423 via peripheral and central mechanisms, was observed 5 As ly demonstrated in our rodent studies, brain insulin reduces SNS outflow to visceral WAT and thereby reduces lipolysis 4.
In follow-up studies in additional cohorts of rats, we could not observe a consistent effect of brain insulin on Hsl activation in sc WAT Mature for adult girl massage. The failure to detect a suppression of Hsl activation in sc WAT Hot Aklavik be attributed to the large variability of Hsl expression between animals in this depot, but it may also indicate that brain insulin regulates lipolysis primarily by controlling visceral WAT metabolism 45.
The latter is in agreement with our present finding that intranasal insulin does not alter lipolysis in sc abdominal tissue as indicated by interstitial glycerol concentrations and activation states of lipolytic enzymes.
The SNS outflow to adipose tissue is depot specific 18which supports the notion that centrally administered insulin may affect primarily visceral, but not sc, WAT tissue 34. In addition, brain insulin may also regulate lipid handling in other organs such as the liver, which our study did Lady want hot sex Corinna examine.
In summary, we demonstrate that insulin delivered to the CNS by intranasal administration acutely suppresses systemic lipolysis in humans. Notably, the suppression of circulating FFAs by intranasal insulin found in our main study with male participants was corroborated by a study in an independent group of subjects that also included women.
Emerging evidence suggests that diabetes and obesity are Looking Real Sex Parkdale Arkansas with reduced insulin sensitivity in the CNS of animals and humans 19 Thus, impaired brain insulin action may contribute to the unrestrained lipolysis that may for the lipotoxicity commonly observed in the obese or diabetic state. Hence, we speculate that restoration of brain insulin aling should improve adipose tissue function in these metabolic disorders.
Aero Pump Hochheim, Germany provided precision nasal air pumps. Lafontan MLangin D. Lipolysis and lipid mobilization in human adipose tissue. Prog Lipid Res. Google Scholar. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell.
Central insulin action regulates peripheral glucose and fat metabolism in mice. J Clin Invest. Brain insulin controls adipose tissue lipolysis and lipogenesis.
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Nat Med. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci. Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions. Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men.
Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism. Diabetes Obes Metab. Int J Obes Lond. Cold-induced alteration of adipokine profile in humans. Ghrelin modulates baroreflex-regulation of sympathetic vasomotor tone in healthy humans.