GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial.

AIMS/HYPOTHESIS: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome). METHODS: In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days, and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center. RESULTS: Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide -0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation. CONCLUSIONS/INTERPRETATION: For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.

Comparison of outcomes of Burch colposuspension and transobturator tape and single incision needleless procedures (DynaMesh®-SIS minor) for the surgical treatment of female stress urinary incontinence patients who underwent combined pelvic reconstructive surgery or hysterectomy.

PURPOSE: Women with stress urinary incontinence (SUI) often require combined pelvic reconstructive surgeries because of shared risk factors of pelvic organ prolapse. The purpose of this study was to evaluate efficacies of Burch colposuspension, transobturator tape (TOT), and single-incision needleless (DynaMesh®-SIS minor) procedures in patients with SUI who also underwent combined pelvic reconstructive surgery or hysterectomy. METHODS: We performed this retrospective cohort study that comprising 122 patients who either underwent Burch colposuspension (n:43), TOT (n:40), or SIS (n:39) procedures along with pelvic reconstructive surgery or hysterectomy between January 2010 and July 2018. During the clinical follow-up, we analyzed cure rates, and surgical success rates of SUI surgery, quality of life, and symptom severity by IIQ-7, UDI-6, SSI, SSQ-8, OAB-V8, and PGI-I scale scores. The primary outcome was surgical success, whereas secondary outcomes included complications and patient-reported outcomes in the quality of life. RESULTS: We found that surgical success rates were higher in Burch group than SIS group and higher in TOT group than in SIS group (88.4% vs 61.5% and 87.5% vs 61.5%, p = 0.003). The quality of life was lower in SIS group than in Burch group. CONCLUSIONS: Both Burch and TOT are effective procedures in patients with SUI who require additional pelvic surgeries. Although surgical outcomes of SIS procedure in patients with SUI who underwent concomitant pelvic surgeries in our study were not promising, further studies with SIS are needed to clarify these observations.

Irisin and leptin concentrations in relation to obesity, and developing type 2 diabetes: A cross sectional and a prospective case-control study nested in the Normative Aging Study.

OBJECTIVE: To investigate the associations between irisin and leptin levels in obesity and insulin resistance in a cross sectional study. To assess the potential role of irisin and leptin as a predictive marker of T2DM using a nested case-control study. METHODS: Both studies were designed within the longitudinal VA NAS cohort. The cross sectional study involved 111 non obese and 105 obese subjects who were subdivided into two groups based on their fasting glucose tolerance. In the nested 1:3 case-control study, 47 subjects with T2DM and 140 non-diabetic controls were selected. Serum samples collected 3-5 years before the diagnosis of T2DM were analyzed. Irisin and leptin concentrations were measured using a validated ELISA and radioimmunoassay respectively. RESULTS: In the cross-sectional study, irisin did not differ between groups based on their fasting glucose tolerance. When subjects were grouped based on obesity status, both irisin and leptin concentrations were significantly higher in obese compared to the non-obese group (p=0.03 and <0.001, respectively). Irisin concentrations positively correlated with leptin concentrations (r= 0.392, P < 0.001). In the nested case control study, leptin concentrations were a significant predictor of developing diabetes (p=0.005) in unadjusted models, but not after correcting for BMI, whereas irisin concentrations did not play a role of comparable significance. CONCLUSIONS: Leptin concentrations are higher in the obese group irrespective of their glucose tolerance. Obese individuals with impaired fasting glucose have higher concentrations of circulating irisin compared to non-obese subjects with normal glucose tolerance. Irisin concentrations do not predict risk of developing diabetes prospectively.

Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: A randomized, placebo-controlled, crossover study.

BACKGROUND: GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics. BASIC PROCEDURES: Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17days (0.6mg for 7days, 1.2mg for 7days and 1.8mg for 3days) of treatment, we also studied changes in fMRI responses to food cues. MAIN FINDINGS: By design, to avoid any confounding by weight changes, subjects were studied for 17days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (p<0.001), decreased percent change in leptin levels (p<0.01) and increased GIP levels (p<0.03) in comparison to placebo treated subjects. Whole brain regressions of functional activity in response to food cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA. PRINCIPAL CONCLUSIONS: We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that could over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials.

Differential Effects of Oral and Intravenous Lipid Administration on Key Molecules Related to Energy Homeostasis.

CONTEXT: The spectrum of lipid-induced changes in the secretion of hormones important in energy homeostasis has not yet been fully elucidated. OBJECTIVE: To identify potential incretin-like effects in response to lipid administration, we examined the short-term effect of iv vs oral lipids on key molecules regulating energy homeostasis. Design, Intervention, and Participants: After a 10-hour overnight fast, 26 subjects were randomized to receive an oral lipid load, a 10% iv lipid emulsion, a 20% iv lipid emulsion, or an iv saline infusion. We obtained blood samples at 30-minute intervals for the first 2 hours and hourly thereafter for a total of 6 hours. MAIN OUTCOME MEASURES: Circulating levels of insulin, glucose, c-peptide, free fatty acids, incretins (glucagon-like peptide-1, gastric inhibitory polypeptide), glucagon, peptide YY, ghrelin, fibroblast growth factor 21, fetuin A, irisin, omentin, and adiponectin were measured. RESULTS: Oral lipid ingestion resulted in higher glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, and peptide YY levels, compared with the other three groups (incremental area under the curve P = .003, P < .001, P < .001, P < .001, respectively). The 20% lipid emulsion, leading to higher free fatty acid levels, resulted in greater insulin, c-peptide, and fibroblast growth factor 21 responses compared with placebo and the other two groups (incremental area under the curve P = .002, P = .005, P < .001, P < .001, respectively). Omentin, adiponectin, fetuin A, and irisin levels were not affected by either mode of lipid administration. CONCLUSIONS: Metabolic responses to lipids depend on the route of administration. Only iv lipids trigger a dose-dependent fibroblast growth factor 21 secretion, which is nonglucagon mediated. Intravenous lipids also induce hyperinsulinemia without concurrent decreases in glucose, a phenomenon observed in insulin-resistant states. Orally administered lipids mostly affect gastrointestinal tract-secreted molecules important in glucose and energy homeostasis such as glucagon, incretins, and peptide YY.

Cord blood irisin levels are positively correlated with birth weight in newborn infants.

BACKGROUND: Irisin is a novel myokine, secreted from skeletal muscle after exercise. Irisin mediates exercise-related energy expenditure by turning white adipose tissue (WAT) into brown adipose tissue (BAT). Thus, irisin is considered as a potential biomarker for obesity and metabolic syndrome. Infants born small for gestational age (SGA) have increased risk for metabolic syndrome. However, the physiologic role of irisin in neonates remains to be studied. OBJECTIVE: To evaluate the association of umbilical cord blood irisin levels with gestational age and birth weight categories in neonates. METHODS: A cross-sectional study of 341 newborns, from 26 to 41weeks' gestation. We collected umbilical cord blood and analyzed plasma for irisin by ELISA. RESULTS: Plasma irisin levels were positively correlated with gestational age (r=0.21, p<0.001), and birth weight Z-score (r=0.18, p<0.001). SGA infants had significantly lower irisin (median [interquartile range] 55.38 [46.56-65.72]ng/mL) compared to appropriate for gestational age infants (64.41 [53.87-76.76]ng/mL) and large for gestational age infants (68.70 [54.78-79.09]ng/mL, p<0.01). The association between SGA and lower irisin remained significant in multivariate analysis independent of gestational age, maternal age, maternal BMI, and gestational diabetes (p=0.03). In singleton infants, irisin was also significantly negatively associated with maternal preeclampsia (p=0.01). CONCLUSIONS: Our results support the notion that irisin may have a physiologic role in neonates. We speculate that decreased levels of irisin in SGA infants may contribute to the development of catch-up growth and metabolic syndrome later in life.

Identification and saturable nature of signaling pathways induced by metreleptin in humans: comparative evaluation of in vivo, ex vivo, and in vitro administration.

Signaling pathways activated by leptin in metabolically important organs have largely been studied only in animal and/or cell culture studies. In this study, we examined whether leptin has similar effects in human peripheral tissues in vivo, ex vivo, and in vitro and whether the response would be different in lean and obese humans. For in vivo leptin signaling, metreleptin was administered and muscle, adipose tissue, and peripheral blood mononuclear cells were taken for analysis of signal activation. Experiments were also done ex vivo and with primary cultured cells in vitro. The signal activation was compared between male versus female and obese versus lean humans. Acute in vivo, ex vivo, and/or in vitro metreleptin administration similarly activated STAT3, AMPK, ERK1/2, Akt, mTOR, NF-κB, and/or IKKα/ß without any differences between male versus female and obese versus lean subjects. All signaling pathways were saturable at ∼30-50 ng/mL, consistent with the clinical evidence showing no additional effect(s) in obese subjects who already have high levels of leptin. Our data provide novel information on downstream effectors of metreleptin action in humans that may have therapeutic implications.

Dietary walnut suppression of colorectal cancer in mice: Mediation by miRNA patterns and fatty acid incorporation.

Colorectal cancer, unlike many other malignancies, may be preventable. Recent studies have demonstrated an inverse association between nut consumption and incidence of colon cancer; however, the underlying mechanisms are not fully understood. An emerging concept suggests that microribonucleic acids (miRNAs) may help explain the relationship between walnut consumption and decreased colorectal neoplasia risk. Seven days after HT-29 colon cancer cell injection, mice were randomized to either control or walnut diets for 25 days of diet treatment. Thirty samples of tumor and of omental adipose were analyzed to determine changes in lipid composition in each dietary group. In the tumors of the walnut-containing diet, we found significant increases in α-linolenic, eicosapentaenoic, docosahexaenoic and total omega-3 acids, and a decrease in arachidonic acid, as compared to the control diet. Final tumor size measured at sacrifice was negatively associated with percentage of total omega-3 fatty acid composition (r=-0.641, P=.001). MicroRNA expression analysis of colorectal tumor tissue revealed decreased expression of miRNAs 1903, 467c and 3068 (P<.05) and increased expression of miRNA 297a* (P=.0059) in the walnut-treated group as compared to control diet. Our results indicate that changes in the miRNA expression profiles likely affect target gene transcripts involved in pathways of anti-inflammation, antivascularization, antiproliferation and apoptosis. We also demonstrate the incorporation of protective fatty acids into colonic epithelium of walnut-fed mice, which may independently alter miRNA expression profiles itself. Future studies of the mechanism of widespread miRNA regulation by walnut consumption are needed to offer potential prognostic and therapeutic targets.

Intracellular leptin signaling following effective weight loss.

AIM: To investigate the effect of ex-vivo leptin treatment before and after weight loss on key-molecules of intracellular leptin signaling in peripheral blood mononuclear cells (PBMCs) of obese women. MATERIALS AND METHODS: Five healthy obese women underwent a 12-week medical nutrition treatment aiming at inducing 10% weight loss. Isolated PBMCs at baseline, and at weeks 8 and 12 were treated with increasing leptin doses (0, 25 and 75 ng/ml) for 30 min. The phosphorylation of signal transducer and activator of transcription (STAT)3, extracellular-signal-regulated kinase (ERK), protein kinase B (Akt) and 5' adenosine monophosphate-activated protein kinase (AMPK) of PBMCs was analyzed using Western blotting. RESULTS: Women lost 10 ± 1% and 13 ± 1% of weight at week 8 and 12, respectively. Circulating leptin and insulin significantly decreased from 39.5 ± 7.7 to 12.2 ± 2.4 ng/ml (p = 0.026) and from 13.0 ± 1.6 to 5.4 ± 0.9 µU/ml (p = 0.005) at week 12, respectively. In the ex vivo study, a significant decrease in STAT3 phosphorylation was observed in the control group after weight loss. Treatment of PBMCs with leptin 75 ng/ml increased significantly ERK, STAT3 and Akt phosphorylation, but no weight loss induced change was observed in response to leptin treatment ex vivo. CONCLUSIONS: A 10%-15% weight loss decreases baseline STAT3 phosphorylation ex vivo, but does not alter the effect of increasing doses of leptin on the incremental intracellular phosphorylation of STAT3, ERK, Akt and AMPK. Supraphysiologic leptin doses (75 ng/ml) result in higher protein phosphorylation compared to either physiologic doses or no treatment, before and after weight loss.

Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines.

AIMS/HYPOTHESIS: Irisin is a novel, myocyte secreted, hormone that has been proposed to mediate the beneficial effects of exercise on metabolism. Irisin is expressed, at lower levels, in human brains and knock-down of the precursor of irisin, FNDC5, decreases neural differentiation of mouse embryonic stem cells. No previous studies have evaluated whether irisin may directly regulate hippocampal neurogenesis in mouse hippocampal neuronal (HN) cells. METHODS: Hippocampal neurogenesis and irisin signaling were studied in vitro using mouse H19-7 HN cell lines. RESULTS: We observed that cell proliferation is regulated by irisin in a dose-dependent manner in mouse H19-7 HN cells. Specifically, physiological concentrations of irisin, 5 to 10nmol/L, had no effect on cell proliferation when compared to control. By contrast, pharmacological concentrations of irisin, 50 to 100nmol/L, increased cell proliferation when compared to control. Similar to these results regarding irisin's effects on cell proliferation, we also observed that only pharmacological concentrations of irisin increased STAT3, but not AMPK and/or ERK, activation. Finally, we observed that irisin did not activate either microtubule-associated protein 2, a specific neurite outgrowth marker, or Synapsin, a specific synaptogenesis marker in mouse H19-7 HN cells. CONCLUSIONS/INTERPRETATIONS: Our data suggest that irisin, in pharmacological concentrations, increases cell proliferation in mouse H19-7 HN cells via STAT3, but not AMPK and/or ERK, signaling pathways. By contrast, neither physiological nor pharmacological concentrations of irisin alter markers of hippocampal neurogenesis in mouse H19-7 HN cell lines.

Circulating irisin in relation to insulin resistance and the metabolic syndrome.

CONTEXT: Irisin, a recently identified hormone, has been proposed to regulate energy homeostasis and obesity in mice. Whether irisin levels are associated with risk of the metabolic syndrome (MetS), cardiometabolic variables, and cardiovascular disease (CVD) risk in humans remains unknown. OBJECTIVE: Our objective was to assess the associations between baseline serum irisin levels and MetS, cardiometabolic variables, and CVD risk. DESIGN, SETTING, AND SUBJECTS: We conducted a comparative cross-sectional evaluation of baseline circulating levels of the novel hormone irisin and the established adipokine adiponectin with MetS, cardiometabolic variables, and CVD risk in a sample of 151 subjects. RESULTS: Baseline irisin levels were significantly higher in subjects with MetS than in subjects without MetS. Irisin was associated negatively with adiponectin (r = -0.4, P < .001) and positively with body mass index (r = 0.22, P = .008), systolic (r = 0.17, P = .04) and diastolic (r = 0.27, P = .001) blood pressure, fasting glucose (r = 0.25, P = .002), triglycerides (r = 0.25, P = .003), and homeostasis model assessment for insulin resistance (r = 0.33, P < .001). After adjustment for potential confounders, including body mass index, subjects in the highest tertile of irisin levels were more likely to have MetS (odds ratio [OR] = 9.44, 95% confidence interval [CI] = 2.66-33.44), elevated fasting blood glucose (OR = 5.80, 95% CI = 1.72-19.60), high triglycerides (OR = 3.89, 95% CI = 1.16-13.03), and low high-density lipoprotein cholesterol (OR = 3.30, 95% CI = 1.18-9.20). Irisin was independently associated with homeostasis model assessment for insulin resistance and general Framingham risk profile in multiple linear regression analyses after adjustment for confounders. Adiponectin demonstrated the expected associations with outcomes. CONCLUSIONS: Irisin is associated with increased risk of MetS, cardiometabolic variables, and CVD in humans, indicating either increased secretion by adipose/muscle tissue and/or a compensatory increase of irisin to overcome an underlying irisin resistance in these subjects.