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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.

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. non-food 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, placebo-controlled crossover study of 24 IU IN OXT included 10 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, non-food 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

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.

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)

The evaluation of pediatric hypoglycemia begins with obtaining a meticulous history and physical exam, and once hypoglycemia has been confirmed, the laboratory evaluation has a critical role in identifying the underlying cause. In children, persistent hypoglycemia is more likely to represent congenital or genetic disorders such as inborn errors of metabolism, abnormalities in insulin secretion, or endocrine deficiencies of cortisol and/or growth hormone. In a recent chart review of children who presented to the emergency room with hypoglycemia without an associated known etiology who had undergone diagnostic evaluation, almost 11% were found to have an underlying high-risk disorder (White K, Truong L, Aaron K, Mushtaq N, Thornton PS. The incidence and etiology of previously undiagnosed hypoglycemic disorders in the emergency department. Pediatr Emerg Care. 2018. https://doi.org/10.1097/PEC.0000000000001634. [Publish Ahead of Print]). The diagnostic blood tests, commonly referred to as the “critical sample,” are pivotal not only for the differential diagnosis of these conditions but also to exclude life-threatening conditions such as fatty acid oxidation defects, hyperinsulinism, and adrenal insufficiency and to provide prompt and appropriate care. In young infants, early recognition and evaluation of recurrent hypoglycemia is imperative to prevent the unwanted neurocognitive sequala that can occur in the setting of hypoglycemia due to congenital hyperinsulinism (Steinkrauss L, Lipman TH, Hendell CD, Gerdes M, Thornton PS, Stanley CA. Effects of hypoglycemia on developmental outcome in children with congenital hyperinsulinism. J Pediatr Nurs. 2005;20(2):109–18; Meissner T, Wendel U, Burgard P, Schaetzle S, Mayatepek E. Long-term follow-up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol. 2003;149(1):43–51). In certain cases, properly planned diagnostic fasts, conducted in a hospital setting, are required for further evaluation. This chapter focuses on the laboratory diagnostic evaluation of hypoglycemia and on the interpretation of the critical sample.

Childhood obesity is a major public health concern with one-third of the youth in United States having either overweight or obesity (Ogden et al., JAMA. 311:806–14, 2014). With the increasing prevalence of youth with severe obesity (Skinner and Skelton, JAMA Pediatr. 168:561–6, 2014), pediatricians are now more likely to manage medical conditions once considered to be “adult diseases” such as prediabetes, type 2 diabetes mellitus (T2DM), dyslipidemia, fatty liver disease, and hypertension. Pediatric caregivers have a unique opportunity to prevent and mitigate the escalation of obesity by intervening early in life. Initial management of obesity at the pediatrician’s office includes lifestyle modification and behavioral-psychological support and is critically important for the amelioration of obesity and prevention of associated comorbidities.

Background: Obesity is a major public health concern with an estimated two thirds of the population being overweight or obese. Women have a higher rate of obesity than men (40% vs. 35%), twice the rate of class 3 obesity (10% vs. 5% with BMI>40), and greater increases in obesity prevalence from 2005-2014. While emerging evidence highlights the role of food motivation circuitry in eating behavior and obesity risk, sex-specific neurobiological mechanisms have not been well defined in this population but are important to guide individual treatment strategies. Using a well-established food motivation functional magnetic resonance (fMRI) paradigm, we ran a preliminary set of analyses to investigate whether sex modulates the brain response to visual presentations of food items. We hypothesized that in a fasted state, women would demonstrate greater blood-oxygen-level-dependent (BOLD) activation in response to food images in reward-related brain regions compared to men. Methods: Twenty-nine adults with obesity (16 female, age (mean±SD): 31.2±4.9 years, and BMI=36.5±4.1 kg/m2) completed fMRI imaging in a 3T scanner while viewing images of food (high-calorie vs. low-calorie), non-food items, and fixation stimuli following a 10-hour overnight fast. Functional MRI data were analyzed using SPM12. Regions of interest included the nucleus accumbens (NAcc), amygdala, caudate, anterior insula (aINS), hypothalamus, putamen, orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), dorsal anterior cingulate cortex (dACC), and supplementary motor area (SMA). Statistical significance of p Results: Women with obesity exhibited greater activation than men in response to food (vs. non-food) stimuli in NAcc (t=2.44, p[uncorrected]=0.011), caudate (t=2.9, p[uncorrected]=0.004), DLPFC (t=3.32, p[uncorrected]=0.001), and dACC (t=3.17, p[uncorrected]=0.002) in a fasted state. There were no regions in which men exhibited greater activation than women. Conclusion: Our preliminary results show that during a fasting state, women with obesity (vs. men) show greater activation in brain regions processing reward (NAcc) and control over behavior (DLPFC, dACC) in response to food (vs. non-food) stimuli. Future studies with larger sample sizes are needed to investigate the link between the highlighted sex differences in neural responses to food in the context of obesity and eating behavior and weight to further inform whether men and women would benefit from different approaches in the treatment of obesity.

Background: The hypothalamic neurohormone oxytocin (OXT), shown to decrease food intake in animal models and men, is a promising novel treatment for obesity. The mechanisms underlying OXT effects on caloric intake in humans are not well understood. We previously showed that in overweight and obese men, 24 IU intranasal (IN) OXT reduced fMRI activation in the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic reward system, in response to high-calorie food vs non-food visual stimuli. To provide further insight into the mechanisms by which OXT exerts its anorexigenic effects, we employed a dynamic method of fMRI analysis, functional connectivity, which refers explicitly to the influence that one neural system exerts over another in a context-dependent manner. We hypothesized that OXT would modulate the functional connectivity of the VTA with key brain areas known to be involved with food sensory and cognitive processing when participants viewed high-calorie foods compared to objects. Methods: In this randomized, double-blind, placebo-controlled crossover study of 24 IU IN OXT, 10 overweight/obese (mean±SD BMI 28.9±0.8 kg/m2), otherwise healthy men age 31.4±1.8 years presented after a 10-h overnight fast. Sixty min after drug administration, subjects started an established fMRI food motivation paradigm that included images of high and low-calorie foods, household objects, and fixation stimuli. Using psychophysiological interaction analysis, the VTA was anatomically defined as the seed region to explore effects of OXT on functional connectivity. Results: Following OXT administration, compared to placebo, participants showed significant attenuation of the functional connectivity between the VTA and insula, parietal operculum, amygdala, anterior and posterior cingulate, and hippocampus in response to viewing high-calorie food stimuli vs. objects (Z≥3.1, cluster corrected, P=0.05). Conclusion: Here we have shown in overweight/obese men that OXT attenuates functional connectivity between the VTA and brain regions associated with the cognitive, sensory and emotional processing of food images. This is particularly relevant to obese individuals, since previous studies have shown greater activation to palatable food images in these areas (e.g., amygdala, hippocampus and insula), and it has been proposed that this hyperactivity of the dopaminergic reward circuit renders obese individuals prone to overeating. Attenuated functional connectivity findings reported here could partially explain the clinically-observed anorexigenic effect of OXT, providing insight into the mechanism through which OXT ameliorates food-cue-induced, CNS-mediated reward anticipation in obese patients. Additional studies are ongoing to further delineate the neural connections underlying the anorexigenic effect of OXT in human obesity.