Intranasal Oxytocin for Obesity.

BACKGROUND: Accumulating preclinical and preliminary translational evidence shows that the hypothalamic peptide oxytocin reduces food intake, increases energy expenditure, and promotes weight loss. It is currently unknown whether oxytocin administration is effective in treating human obesity. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned adults with obesity 1:1 (stratified by sex and obesity class) to receive intranasal oxytocin (24 IU) or placebo four times daily for 8 weeks. The primary end point was change in body weight (kg) from baseline to week 8. Key secondary end points included change in body composition (total fat mass [g], abdominal visceral adipose tissue [cm2], and liver fat fraction [proportion; range, 0 to 1; higher values indicate a higher proportion of fat]), and resting energy expenditure (kcal/day; adjusted for lean mass) from baseline to week 8 and caloric intake (kcal) at an experimental test meal from baseline to week 6. RESULTS: Sixty-one participants (54% women; mean age ± standard deviation, 33.6 ± 6.2 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 36.9 ± 4.9) were randomly assigned. There was no difference in body weight change from baseline to week 8 between oxytocin and placebo groups (0.20 vs. 0.26 kg; P=0.934). Oxytocin (vs. placebo) was not associated with beneficial effects on body composition or resting energy expenditure from baseline to week 8 (total fat: difference [95% confidence interval], 196.0 g [-1036 to 1428]; visceral fat: 3.1 cm2 [-11.0 to 17.2]; liver fat: -0.01 [-0.03 to 0.01]; resting energy expenditure: -64.0 kcal/day [-129.3 to 1.4]). Oxytocin compared with placebo was associated with reduced caloric intake at the test meal (-31.4 vs. 120.6 kcal; difference [95% confidence interval], -152.0 kcal [-302.3 to -1.7]). There were no serious adverse events. Incidence and severity of adverse events did not differ between groups. CONCLUSIONS: In this randomized, placebo-controlled trial in adults with obesity, intranasal oxytocin administered four times daily for 8 weeks did not reduce body weight. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT03043053.).

Platelet count and risk of severe illness in hospitalised children with Influenza-Like illness.

AIM: To examine the clinical significance of thrombocytosis (platelets > 500 × 109 /L) in admitted children with an influenza-like illness. METHODS: We performed a database analysis consisting of patients evaluated at our medical centers with an influenza-like illness between 2009 and 2013. We included paediatric patients and examined the association between platelet count, respiratory viral infections, and admission outcomes (hospital length of stay and admission to the paediatric intensive care unit) using regression models adjusting for multiple variables. RESULTS: A total of 5171 children were included in the study cohort (median age 0.8 years; interquartile range, 0.2-1.8; 58% male). Younger age, and not the type of viral infection, was associated with a high platelet count (p < 0.001). Elevated platelet count independently predicted admission outcomes (p ≤ 0.05). The presence of thrombocytosis was associated with an increased risk for a prolonged length of stay (odds ratio = 1.2; 95% Confidence interval = 1.1 to 1.4; p = 0.003) and admission to the paediatric intensive care unit (odds ratio = 1.5; 95% Confidence interval = 1.1 to 2.0; p = 0.002). CONCLUSION: In children admitted with an influenza-like illness, a high platelet count is an independent predictor of admission outcomes. Platelet count may be used to improve risk assessment and management decisions in these paediatric patients.

A randomized, double-blind, placebo-controlled clinical trial of 8-week intranasal oxytocin administration in adults with obesity: Rationale, study design, and methods.

BACKGROUND: Obesity affects more than one-third of adults in the U.S., and effective treatment options are urgently needed. Oxytocin administration induces weight loss in animal models of obesity via effects on caloric intake, energy expenditure, and fat metabolism. We study intranasal oxytocin, an investigational drug shown to reduce caloric intake in humans, as a potential novel treatment for obesity. METHODS: We report the rationale, design, methods, and biostatistical analysis plan of a randomized, double-blind, placebo-controlled clinical trial of intranasal oxytocin for weight loss (primary endpoint) in adults with obesity. Participants (aged 18-45 years) were randomly allocated (1:1) to oxytocin (four times daily over eight weeks) versus placebo. Randomization was stratified by biological sex and BMI (30 to <35, 35 to <40, ≥40 kg/m2). We investigate the efficacy, safety, and mechanisms of oxytocin administration in reducing body weight. Secondary endpoints include changes in resting energy expenditure, body composition, caloric intake, metabolic profile, and brain activation via functional magnetic resonance imaging in response to food images and during an impulse control task. Safety and tolerability (e.g., review of adverse events, vital signs, electrocardiogram, comprehensive metabolic panel) are assessed throughout the study and six weeks after treatment completion. RESULTS: Sixty-one male and female participants aged 18-45 years were randomized (mean age 34 years, mean BMI 37 kg/m2). The study sample is diverse with 38% identifying as non-White and 20% Hispanic. CONCLUSION: Investigating intranasal oxytocin's efficacy, safety, and mechanisms as an anti-obesity medication will advance the search for optimal treatment strategies for obesity and its associated severe sequelae.

Neurobiology of Avoidant/Restrictive Food Intake Disorder in Youth with Overweight/Obesity Versus Healthy Weight.

OBJECTIVE: Avoidant/restrictive food intake disorder (ARFID) occurs across the weight spectrum, however research addressing the coexistesnce of ARFID with overweight/obesity (OV/OB) is lacking. We aimed to establish co-occurrence of OV/OB and ARFID and to characterize divergent neurobiological features of ARFID by weight. METHOD: Youth with full/subthreshold ARFID (12 with healthy weight [HW], 11 with OV/OB) underwent fasting brain fMRI scan while viewing food/non-food images (M age = 16.92 years, 65% female, 87% white). We compared groups on BOLD response to high-calorie foods (HCF) (vs. objects) in food cue processing regions of interest. Following fMRI scanning, we evaluated subjective hunger pre- vs. post-meal. We used a mediation model to explore the association between BMI, brain activation, and hunger. RESULTS: Participants with ARFID and OV/OB demonstrated significant hyperactivation in response to HCF (vs. objects) in the orbitofrontal cortex (OFC) and anterior insula compared with HW participants with ARFID. Mediation analysis yielded a significant indirect effect of group (HW vs. OV/OB) on hunger via OFC activation (effect = 18.39, SE = 11.27, 95% CI [-45.09, -3.00]), suggesting that OFC activation mediates differences in hunger between ARFID participants with HW and OV/OB. CONCLUSIONS: Compared to youth with ARFID and HW, those with OV/OB demonstrate hyperactivation of brain areas critical for the reward value of food cues. Postprandial changes in subjective hunger depend on BMI and are mediated by OFC activation to food cues. Whether these neurobiological differences contribute to selective hyperphagia in ARFID presenting with OV/OB and represent potential treatment targets is an important area for future investigation.

Oxytocin, eating behavior, and metabolism in humans.

The hypothalamic peptide oxytocin has been increasingly recognized as a hormone and neurotransmitter with important effects on energy intake, metabolism, and body weight and is under investigation as a potential novel therapeutic agent for obesity. The main neurons producing oxytocin and expressing the oxytocin receptor are strategically located in brain areas known to be critically involved in homeostatic energy balance as well as hedonic and motivational aspects of eating behavior. In this chapter, we will review the central and peripheral physiology of oxytocin and the interaction of oxytocin with key hormones and neural circuitries that affect food intake and metabolism. Next, we will synthesize the available data on endogenous oxytocin levels related to caloric intake, body weight, and metabolic status. We will then review the effects of exogenous oxytocin administration on eating behavior, body weight, and metabolism in humans, including in healthy individuals as well as specific populations with suspected perturbations involving oxytocin pathways. Finally, we will address the promise and fundamental challenges of translating this line of research to clinical care.

The Effects of Oxytocin on Appetite Regulation, Food Intake and Metabolism in Humans.

The hypothalamic peptide oxytocin and its receptor are involved in a range of physiological processes, including parturition, lactation, cell growth, wound healing, and social behavior. More recently, increasing evidence has established the effects of oxytocin on food intake, energy expenditure, and peripheral metabolism. In this review, we provide a comprehensive description of the central oxytocinergic system in which oxytocin acts to shape eating behavior and metabolism. Next, we discuss the peripheral beneficial effects oxytocin exerts on key metabolic organs, including suppression of visceral adipose tissue inflammation, skeletal muscle regeneration, and bone tissue mineralization. A brief summary of oxytocin actions learned from animal models is presented, showing that weight loss induced by chronic oxytocin treatment is related not only to its anorexigenic effects, but also to the resulting increase in energy expenditure and lipolysis. Following an in-depth discussion on the technical challenges related to endogenous oxytocin measurements in humans, we synthesize data related to the association between endogenous oxytocin levels, weight status, metabolic syndrome, and bone health. We then review clinical trials showing that in humans, acute oxytocin administration reduces food intake, attenuates fMRI activation of food motivation brain areas, and increases activation of self-control brain regions. Further strengthening the role of oxytocin in appetite regulation, we review conditions of hypothalamic insult and certain genetic pathologies associated with oxytocin depletion that present with hyperphagia, extreme weight gain, and poor metabolic profile. Intranasal oxytocin is currently being evaluated in human clinical trials to learn whether oxytocin-based therapeutics can be used to treat obesity and its associated sequela. At the end of this review, we address the fundamental challenges that remain in translating this line of research to clinical care.

Modulation of neural fMRI responses to visual food cues by overeating and fasting interventions: A preliminary study.

Neural processing of visual food stimuli is perturbated at extremes of weight. Human fMRI studies investigating diet effects on neural processing of food cues could aid in understanding altered brain activation in conditions of under- and overnutrition. In this preliminary study, we examined brain activity changes in response to 10 days of high-calorie-diet (HCD), followed by 10 days of fasting, hypothesizing that HCD would decrease activation in homeostatic and reward regions, while fasting would increase activation in homeostatic/reward regions and decrease activation of self-control regions. Seven adults completed fMRI scanning during a food-cue paradigm (high- and low-calorie food images and nonfood objects), pre- and post-10-day HCD. Six adults completed fMRI scanning pre- and post-10-day fasting. BOLD response changes for contrasts of interest pre- versus post-intervention in regions of interest were examined (peak-level significance set at p(FWE)<0.05). BMI increased by 6.8% and decreased by 8.1% following HCD and fasting, respectively. Following HCD, BOLD response in the hypothalamus (homeostatic control), was attenuated at trend level in response to high- versus low-calorie foods. Following fasting, BOLD response to food versus objects in inhibitory-control areas (dorsolateral prefrontal cortex) was reduced, whereas the activation of homeostatic (hypothalamus), gustatory, and reward brain areas (anterior insula and orbitofrontal cortex) increased. Overfeeding and fasting for 10 days modulate brain activity in response to food stimuli, suggesting that in healthy adults, changes in energy balance affect saliency and reward value of food cues. Future studies are required to understand this interaction in states of unhealthy weight.

Oxytocin reduces the functional connectivity between brain regions involved in eating behavior in men with overweight and obesity.

BACKGROUND: Oxytocin (OXT), shown to decrease food intake in animal models and men, is a promising novel treatment for obesity. We have shown that in men with overweight and obesity, intranasal (IN) OXT reduced the functional magnetic resonance imaging (fMRI) blood oxygenation level-dependent signal in the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic reward system, in response to high-calorie food vs. nonfood images. Here, we employed functional connectivity fMRI analysis, which measures the synchrony in activation between neural systems in a context-dependent manner. We hypothesized that OXT would attenuate the functional connectivity of the VTA with key food motivation brain areas only when participants viewed high-calorie food stimuli. METHODS: This randomized, double-blind, and placebo-controlled crossover study of 24 IU IN OXT included ten men with overweight or obesity (mean ± SEM BMI: 28.9 ± 0.8 kg/m2). Following drug administration, subjects completed an fMRI food motivation paradigm including images of high and low-calorie foods, nonfood objects, and fixation stimuli. A psychophysiological interaction analysis was performed with the VTA as seed region. RESULTS: Following OXT administration, compared with placebo, participants exhibited significantly attenuated functional connectivity between the VTA and the insula, oral somatosensory cortex, amygdala, hippocampus, operculum, and middle temporal gyrus in response to viewing high-calorie foods (Z ≥ 3.1, cluster-corrected, p < 0.05). There was no difference in functional connectivity between VTA and these brain areas when comparing OXT and placebo for low-calorie food, nonfood, and fixation images. CONCLUSION: In men with overweight and obesity, OXT attenuates the functional connectivity between the VTA and food motivation brain regions in response to high-calorie visual food images. These findings could partially explain the observed anorexigenic effect of OXT, providing insight into the mechanism through which OXT ameliorates food cue-induced reward anticipation in patients with obesity. Additional studies are ongoing to further delineate the anorexigenic effect of OXT in obesity.

Physical activity in adolescents and children and relationship to metabolic health.

PURPOSE OF REVIEW: To summarize the recent developments relating to the role of physical activity in improving insulin resistance and metabolic syndrome in children and adolescents. RECENT FINDINGS: The current literature strengthens previous findings on the relationship between physical activity and metabolic health in children; suggests a protective role for physical activity in the setting of obesity; examines population-specific findings; addresses specific effects of different modalities of physical activity in improving health; reveals potential mediators in the relationship between physical activity and metabolic health; and suggests new markers of metabolic health that could potentially be used as outcomes in future physical activity studies. SUMMARY: Recent research generally confirms the role of physical activity in decreasing insulin resistance and metabolic syndrome in children and adolescents. However, the current literature is limited by unstandardized research methods and definitions, and also aggregation of different age groups, genders, and weight status. Future research should address these issues to offer targeted physical activity interventions.