Oxytocin Administration Increases Proactive Control in Men with Overweight or Obesity: A Randomized, Double-Blind, Placebo-Controlled Crossover Study.

OBJECTIVE: Preclinical and clinical evidence suggests that oxytocin administration decreases food intake and weight. The mechanisms underlying the anorexigenic effects of oxytocin in humans are unknown but critical to study to consider oxytocin as a neurohormonal weight loss treatment. Complementing ongoing research into metabolic and food motivation mechanisms of oxytocin, this study hypothesized that in humans, oxytocin improves cognitive control over behavior. METHODS: In a randomized, double-blind, placebo-controlled crossover study of 24-IU single-dose intranasal oxytocin, 10 men with overweight or obesity completed a stop-signal task assessing ability and strategy to suppress behavioral impulses, in which they performed a choice-reaction task (go task) but had to withhold their response when prompted (stop task). It was hypothesized that oxytocin would improve suppression of behavioral impulses. RESULTS: After receiving oxytocin, compared with placebo, participants showed increased reaction times in the go task (mean [M] = 936 milliseconds vs. 833 millseconds; P = 0.012; 95% CI: 29 to 178) and displayed fewer stop errors (M = 36.41% vs. 41.15%; P = 0.049; 95% CI: -9.43% to -0.03%). CONCLUSIONS: Oxytocin triggers increased proactive control over behavior. Future studies need to further characterize the impact of oxytocin on cognitive control and investigate its potential role in the anorexigenic effects of oxytocin in human obesity.

Medical comorbidities and endocrine dysfunction in low-weight females with avoidant/restrictive food intake disorder compared to anorexia nervosa and healthy controls.

OBJECTIVE: To improve our understanding of medical complications and endocrine alterations in patients with low-weight avoidant/restrictive food intake disorder (ARFID) and how they may differ from those in anorexia nervosa (AN) and healthy controls (HC). METHOD: We performed an exploratory cross-sectional study comparing low-weight females with ARFID (n = 20) with females with AN (n = 42) and HC (n = 49) with no history of an eating disorder. RESULTS: We found substantial overlap in medical comorbidities and endocrine features in ARFID and AN, but with earlier onset of aberrant eating behaviors in ARFID. We also observed distinct medical and endocrine alterations in ARFID compared to AN, such as a greater prevalence of asthma, a lower number of menses missed in the preceding 9 months, higher total T3 levels, and lower total T4 : total T3 ratio; these differences persisted after adjusting for age and might reflect differences in pathophysiology, acuity of weight fluctuations, and/or nutritional composition of food consumed. CONCLUSION: These results highlight the need for prompt diagnosis and intensive therapeutic intervention from disease onset in ARFID.

Exposure to American Football and Neuropsychiatric Health in Former National Football League Players: Findings From the Football Players Health Study.

BACKGROUND: Former American football players have a higher prevalence of cognitive impairment than that of the US general population. It remains unknown what aspects of playing football are associated with neuropsychiatric outcomes. HYPOTHESIS: It was hypothesized that seasons of professional football, playing position, and experience of concussions were associated with cognition-related quality of life (QOL) and indicators of depression and anxiety. STUDY DESIGN: Descriptive epidemiology study. METHODS: The authors examined whether seasons of professional football, playing position, and experience of concussions, as measured by self-report of 10 symptoms, were associated with cognition-related QOL and indicators of depression and anxiety in a cross-sectional survey conducted 2015 to 2017. Cognition-related QOL was measured by the short form of the Quality of Life in Neurological Disorders: Applied Cognition-General Concerns. The Patient Health Questionnaire-4 measured depression and anxiety symptoms. Of 13,720 eligible men with apparently valid contact information, 3506 players returned a questionnaire at the time of this analysis (response rate = 25.6%). RESULTS: Seasons of professional play (risk ratio [RR] per 5 seasons = 1.19, 95% CI = 1.06-1.34) and playing position were associated with cognition-related QOL. Each 5 seasons of play was associated with 9% increased risk of indicators of depression at borderline statistical significance (P = .05). When compared with former kickers, punters, and quarterbacks, men who played any other position had a higher risk of poor cognition-related QOL, depression, and anxiety. Concussion symptoms were strongly associated with poor cognition-related QOL (highest concussion quartile, RR = 22.3, P < .001), depression (highest quartile, RR = 6.0, P < .0001), and anxiety (highest quartile, RR = 6.4, P < .0001), even 20 years after last professional play. CONCLUSION: The data suggest that seasons of play and playing position in the NFL are associated with lasting neuropsychiatric health deficits. Additionally, poor cognition-related QOL, depression, and anxiety appear to be associated with concussion in the long term.

Low Plasma Oxytocin Levels and Increased Psychopathology in Hypopituitary Men With Diabetes Insipidus.

CONTEXT: Oxytocin (OT) and vasopressin share anatomical pathways of synthesis and secretion, and patients with central diabetes insipidus (CDI) presumably are at risk for OT deficiency. However, an OT-deficient state in hypopituitary patients has not been established. OBJECTIVES: We hypothesized that men with CDI compared to patients with similar anterior pituitary deficiencies (APD) but no CDI and healthy controls (HC) of similar age and body mass index, would have lower plasma OT levels, associated with increased psychopathology. DESIGN: Cross-sectional. SETTING: Clinical research center. PARTICIPANTS: Sixty-two men (20 CDI, 20 APD, 22 HC), age 18 to 60 years. INTERVENTIONS: Frequent sampling of blood every 5 minutes for OT over 1 hour and validated questionnaires to assess psychopathology. MAIN OUTCOMES: Pooled plasma OT levels; depressive, anxiety, and alexithymia symptoms; and quality of life. RESULTS: The mean 1-hour pool of fasting OT levels was lower in CDI compared with APD and HC (P = 0.02 and P = 0.009, respectively), with no differences between APD and HC (P = 0.78). Symptoms of depression, anxiety, and alexithymia were more pronounced in CDI than in HC (P = 0.001, P = 0.004, and P = 0.02, respectively). Although CDI and APD reported worse physical health compared with HC (P = 0.001 and P = 0.005) with no differences between APD and CDI, only CDI reported worse mental health compared with HC (P = 0.009). CONCLUSIONS: We have demonstrated low plasma OT levels and increased psychopathology in hypopituitary men with CDI, suggestive of a possible OT-deficient state. Larger studies of both sexes are required to confirm these findings and clinically characterize hypopituitary patients with OT deficiency.

Effects of Intranasal Oxytocin on the Blood Oxygenation Level-Dependent Signal in Food Motivation and Cognitive Control Pathways in Overweight and Obese Men.

Recent research indicates that the hypothalamic neuropeptide hormone oxytocin is a key central nervous system factor in the regulation of food intake and weight. However, the mechanisms underlying the anorexigenic effects of oxytocin in humans are unknown and critical to study to consider oxytocin as a neurohormonal weight loss treatment. We performed a randomized, double-blind, placebo-controlled crossover study with single-dose intranasal oxytocin (24 IU) in ten overweight or obese, otherwise healthy men. Following oxytocin/placebo administration, participants completed an established functional magnetic resonance imaging food motivation paradigm. We hypothesized that oxytocin would reduce the blood oxygenation level-dependent (BOLD) signal to high-calorie food vs non-food visual stimuli in the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic reward system. Following oxytocin administration, compared to placebo, participants showed bilateral VTA hypoactivation to high-calorie food stimuli. A secondary exploratory whole-brain analysis revealed hypoactivation in additional hedonic (orbitofrontal cortex, insula, globus pallidus, putamen, hippocampus, and amygdala) and homeostatic (hypothalamus) food motivation and hyperactivation in cognitive control (anterior cingulate and frontopolar cortex) brain regions following oxytocin administration vs placebo. Oxytocin administration reduces the BOLD signal in reward-related food motivation brain regions, providing a potential neurobiological mechanism for the anorexigenic oxytocin effects in humans. Furthermore, our data indicate that oxytocin administration reduces activation in homeostatic and increases activation in cognitive control brain regions critically involved in regulating food intake and resolving affective conflict, respectively. Future studies are required to link these changes in brain activation to oxytocin effects on food intake and weight.

Low oxytocin levels are related to alexithymia in anorexia nervosa.

OBJECTIVE: Anorexia nervosa is associated with social-emotional functioning deficits and low levels of the social neurohormone oxytocin, even after weight gain. The relationship between low oxytocin levels and social-emotional functioning impairment has not been studied. METHOD: We performed a cross-sectional study of 79 women (19 who were less than 85% of ideal body weight [IBW] with anorexia nervosa [AN], 26 who were 90-120% IBW with a history of AN [AN-WR], and 34 who were 90-120% IBW with no eating disorder history [H]). We administered the Eating Disorder Examination-Questionnaire (EDE-Q), Leibowitz Social Anxiety Scale-Self Report (LSAS-SR), Dimensional Assessment of Personality Pathology-Basic Questionnaire (DAPP-BQ; suspiciousness and insecure attachment subscales), and the Toronto Alexithymia Scale (TAS-20). We also analyzed fasting serum oxytocin levels. RESULTS: Most measures of social-emotional functioning showed impairment in women with AN and AN-WR compared to H. Oxytocin levels were low in AN-WR compared to H. Across groups, low oxytocin levels were associated with difficulty identifying feelings (r = -.45, p = .008) and overall alexithymia (r = -.34, p = .0489). DISCUSSION: We speculate that low oxytocin levels may contribute to alexithymia in women with anorexia nervosa.

Oxytocin and Its Relationship to Body Composition, Bone Mineral Density, and Hip Geometry Across the Weight Spectrum.

Context: Oxytocin (OXT), an anorexigenic hypothalamic hormone anabolic to bone, may reflect energy availability. Basal serum OXT levels are lower in anorexia nervosa (AN, state of energy deficit) than healthy controls (HC) and negatively associated with spine bone mineral density (BMD). Reports are conflicting regarding OXT levels in overweight/obesity (OB, state of energy excess). Relationships between OXT and BMD in OB and hip geometry across the weight spectrum are unknown. Objective: To determine whether overnight serum OXT levels are (1) elevated in OB and (2) associated with body composition, BMD, and hip geometry across the weight spectrum. Design: Cross-sectional. Setting: Clinical research center. Participants: Fifty-nine women, ages 18 to 45 years: amenorrheic AN (N = 16), eumenorrheic HC (N = 24), eumenorrheic OB (N = 19). Main Outcome Measures: Serum sampled every 20 minutes from 8 pm to 8 am and pooled for integrated overnight OXT levels. Body composition, BMD, and hip structural analysis measured by dual x-ray absorptiometry. Results: OXT levels were lowest in AN, higher in HC, and highest in OB (P ≤ 0.02). There were positive associations between OXT and (1) body mass index (P = 0.0004); (2) total, visceral, and subcutaneous fat (P ≤ 0.0002); (3) spine and hip BMD Z-scores (P ≤ 0.01); and (4) favorable hip geometry, namely buckling ratio (P ≤ 0.05). In a subset analysis of HC and OB, relationships between OXT and body composition, but not bone parameters, remained significant. Conclusions: These data suggest OXT is a marker of energy availability and may be a mediator of bone density, structure, and strength. OXT pathways may provide targets for obesity and osteoporosis treatment.

Oxytocin reduces caloric intake in men.

OBJECTIVE: Preclinical studies indicate that oxytocin is anorexigenic and has beneficial metabolic effects. Oxytocin effects on nutrition and metabolism in humans are not well defined. It was hypothesized that oxytocin would reduce caloric intake and appetite and alter levels of appetite-regulating hormones. Metabolic effects of oxytocin were also explored. METHODS: A randomized, placebo-controlled crossover study of single-dose intranasal oxytocin (24 IU) in 25 fasting healthy men was performed. After oxytocin/placebo, subjects selected breakfast from a menu and were given double portions. Caloric content of food consumed was measured. Visual analog scales were used to assess appetite, and blood was drawn for appetite-regulating hormones, insulin, and glucose before and after oxytocin/placebo. Indirect calorimetry assessed resting energy expenditure (REE) and substrate utilization. RESULTS: Oxytocin reduced caloric intake with a preferential effect on fat intake and increased levels of the anorexigenic hormone cholecystokinin without affecting appetite or other appetite-regulating hormones. There was no effect of oxytocin on REE. Oxytocin resulted in a shift from carbohydrate to fat utilization and improved insulin sensitivity. CONCLUSIONS: Intranasal oxytocin reduces caloric intake and has beneficial metabolic effects in men without concerning side effects. The efficacy and safety of sustained oxytocin administration in the treatment of obesity warrants investigation.

Irisin levels are lower in young amenorrheic athletes compared with eumenorrheic athletes and non-athletes and are associated with bone density and strength estimates.

Irisin and FGF21 are novel hormones implicated in the "browning" of white fat, thermogenesis, and energy homeostasis. However, there are no data regarding these hormones in amenorrheic athletes (AA) (a chronic energy deficit state) compared with eumenorrheic athletes (EA) and non-athletes. We hypothesized that irisin and FGF21 would be low in AA, an adaptive response to low energy stores. Furthermore, because (i) brown fat has positive effects on bone, and (ii) irisin and FGF21 may directly impact bone, we hypothesized that bone density, structure and strength would be positively associated with these hormones in athletes and non-athletes. To test our hypotheses, we studied 85 females, 14-21 years [38 AA, 24 EA and 23 non-athletes (NA)]. Fasting serum irisin and FGF21 were measured. Body composition and bone density were assessed using dual energy X-ray absorptiometry, bone microarchitecture using high resolution peripheral quantitative CT, strength estimates using finite element analysis, resting energy expenditure (REE) using indirect calorimetry and time spent exercising/week by history. Subjects did not differ for pubertal stage. Fat mass was lowest in AA. AA had lower irisin and FGF21 than EA and NA, even after controlling for fat and lean mass. Across subjects, irisin was positively associated with REE and bone density Z-scores, volumetric bone mineral density (total and trabecular), stiffness and failure load. FGF21 was negatively associated with hours/week of exercise and cortical porosity, and positively with fat mass and cortical volumetric bone density. Associations of irisin (but not FGF21) with bone parameters persisted after controlling for potential confounders. In conclusion, irisin and FGF21 are low in AA, and irisin (but not FGF21) is independently associated with bone density and strength in athletes.

Oxytocin secretion is related to measures of energy homeostasis in young amenorrheic athletes.

CONTEXT: Oxytocin has been implicated in the modulation of energy metabolism in animals. Oxytocin knockout mice develop obesity without a change in food intake, suggesting that a lack of oxytocin may reduce metabolic rate. Furthermore, administration of oxytocin centrally reduces food intake in rats, an effect reversed by an oxytocin antagonist, implying that oxytocin may regulate appetite and energy intake. We have previously demonstrated that young female athletes (in a higher energy expenditure state than nonathletes) have low nocturnal oxytocin compared with nonathletes. Whether oxytocin is associated with measures of energy homeostasis in athletes is unknown. OBJECTIVE: We hypothesized that oxytocin, a signal for energy availability, would be associated with other measures of energy homeostasis in young female athletes. DESIGN AND SETTING: We performed a cross-sectional study of 45 females, aged 14-21 years [15 amenorrheic athletes (AA), 15 eumenorrheic athletes, and 15 nonathletes] of comparable body mass index. METHODS: Dual x-ray absorptiometry was performed to assess body composition. Indirect calorimetry was used to measure resting energy expenditure (REE). Fasting levels of oxytocin, energy homeostasis hormones irisin and fibroblast growth factor-21, and appetite-regulating hormone peptide YY were obtained. RESULTS: In AA, oxytocin secretion was positively correlated with surrogate measures of energy availability, including weight (r = 0.65, P = .009) and body mass index (r = 0.61, P = .016). Furthermore, oxytocin was associated with REE (r = 0.80, P = .0003), independent of lean mass, and with irisin (r = 0.74, P = .002) and fibroblast growth factor-21 (r = 0.58, P = .024). In eumenorrheic athletes, oxytocin was associated with REE (r = 0.59, P = .021), independent of lean mass. In nonathletes, oxytocin secretion was not significantly associated with measures of energy homeostasis. CONCLUSIONS: In AA, oxytocin secretion is associated with measures of energy availability and expenditure, suggesting that oxytocin may be involved in regulation of energy balance in energy deficient states. Further studies determining the role of oxytocin in appetite and energy homeostasis in athletes are warranted.

Parathyroid hormone (PTH)/PTH-related peptide type 1 receptor (PPR) signaling in osteocytes regulates anabolic and catabolic skeletal responses to PTH.

Parathyroid hormone (PTH) is the only Food and Drug Administration-approved anabolic agent to treat osteoporosis; however, the cellular targets of PTH action in bone remain controversial. PTH modulates bone turnover by binding to the PTH/PTH-related peptide (PTHrP) type 1 receptor (PPR), a G-protein-coupled receptor highly expressed in bone and kidneys. Osteocytes, the most abundant cells in adult bone, also express PPR. However, the physiological relevance of PPR signaling in osteocytes remains to be elucidated. Toward this goal, we generated mice with PPR deletion in osteocytes (Ocy-PPRKO). Skeletal analysis of these mice revealed a significant increase in bone mineral density and trabecular and cortical bone parameters. Osteoblast activities were reduced in these animals, as demonstrated by decreased collagen type I α1 mRNA and receptor activator of NF-κB ligand (RANKL) expression. Importantly, when subjected to an anabolic or catabolic PTH regimen, Ocy-PPRKO animals demonstrated blunted skeletal responses. PTH failed to suppress SOST/Sclerostin or induce RANKL expression in Ocy-PPRKO animals compared with controls. In vitro, osteoclastogenesis was significantly impaired in Ocy-PPRKO upon PTH administration, indicating that osteocytes control osteoclast formation through a PPR-mediated mechanism. Taken together, these data indicate that PPR signaling in osteocytes is required for bone remodeling, and receptor signaling in osteocytes is needed for anabolic and catabolic skeletal responses.