Acquired hypothalamic obesity: A clinical overview and update.

Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by impairment in the key brain pathways that regulate energy intake and expenditure, autonomic nervous system function, and peripheral hormonal signalling. HO often occurs in the context of hypothalamic syndrome, a constellation of symptoms that follow from disruption of hypothalamic functions, for example, temperature regulation, sleep-wake circadian control, and energy balance. Genetic forms of HO, including the monogenic obesity syndromes, often impact central leptin-melanocortin pathways. Acquired forms of HO occur as a result of tumours impacting the hypothalamus, such as craniopharyngioma, surgery or radiation to treat those tumours, or other forms of hypothalamic damage, such as brain injury impacting the region. Risk for severe obesity following hypothalamic injury is increased with larger extent of hypothalamic damage or lesions that contain the medial and posterior hypothalamic nuclei that support melanocortin signalling pathways. Structural damage in these hypothalamic nuclei often leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue, the collective effect of which is rapid weight gain. Individuals with hyperphagia are perpetually hungry. They do not experience fullness at the end of a meal, nor do they feel satiated after meals, leading them to consume larger and more frequent meals. To date, most efforts to treat HO have been disappointing and met with limited, if any, long-term success. However, new treatments based on the distinct pathophysiology of disturbed energy homeostasis in acquired HO may hold promise for the future.

Treatment of hypothalamic obesity in people with hypothalamic injury: new drugs are on the horizon.

Hypothalamic obesity (HO) is a complex and rare disorder affecting multiple regulatory pathways of energy intake and expenditure in the brain as well as the regulation of the autonomic nervous system and peripheral hormonal signaling. It can be related to monogenic obesity syndromes which often affect the central leptin-melanocortin pathways or due to injury of the hypothalamus from pituitary and hypothalamic tumors, such as craniopharyngioma, surgery, trauma, or radiation to the hypothalamus. Traditional treatments of obesity, such as lifestyle intervention and specific diets, are still a therapeutic cornerstone, but often fail to result in meaningful and sustained reduction of body mass index. This review will give an update on pharmacotherapies of HO related to hypothalamic injury. Recent obesity drug developments are promising for successful obesity intervention outcomes.

A peptide triple agonist of GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors promotes glycemic control and weight loss.

Mechanisms underlying long-term sustained weight loss and glycemic normalization after obesity surgery include changes in gut hormone levels, including glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). We demonstrate that two peptide biased agonists (GEP44 and GEP12) of the GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors (GLP-1R, Y1-R, and Y2-R, respectively) elicit Y1-R antagonist-controlled, GLP-1R-dependent stimulation of insulin secretion in both rat and human pancreatic islets, thus revealing the counteracting effects of Y1-R and GLP-1R agonism. These agonists also promote insulin-independent Y1-R-mediated glucose uptake in muscle tissue ex vivo and more profound reductions in food intake and body weight than liraglutide when administered to diet-induced obese rats. Our findings support a role for Y1-R signaling in glucoregulation and highlight the therapeutic potential of simultaneous receptor targeting to achieve long-term benefits for millions of patients.

Novel Long-Acting Oxytocin Analog with Increased Efficacy in Reducing Food Intake and Body Weight.

Oxytocin (OXT) analogues have been designed to overcome the limitation of the short half-life of the native OXT peptide. Here, we tested ASK2131 on obesity related outcomes in diet-induced obese (DIO) Sprague Dawley rats. In vitro function assays were conducted. The effects of daily subcutaneous injections of ASK2131 vs. OXT and pair-feeding were assessed on food intake and body weight in vivo. ASK2131 is a longer-lasting OXT analog with improved pharmacokinetics compared to OXT (T1/2: 2.3 vs. 0.12 h). In chronic 22-day administration, ASK2131 was administered at 50 nmol/kg, while OXT doses were titrated up to 600 nmol/kg because OXT appeared to be less effective at reducing energy intake relative to ASK2131 at equimolar doses. After 22 days, vehicle-treated animals gained 4.5% body weight, OXT rats maintained their body weight, while those treated with ASK2131 declined in weight continuously over the 22-day period, leading to a 6.6 ± 1.3% reduction (mean ± standard error) compared to baseline. Compared to their pair-fed counterparts, ASK2131-treated rats showed a more pronounced reduction in body weight through most of the study. In summary, ASK2131 is a promising OXT-based therapeutic, with extended in vivo stability and improved potency leading to a profound reduction in body weight partly explained by reduced food intake.

Impaired Brain Satiety Responses After Weight Loss in Children With Obesity.

CONTEXT: Obesity interventions often result in increased motivation to eat. OBJECTIVE: We investigated relationships between obesity outcomes and changes in brain activation by visual food cues and hormone levels in response to obesity intervention by family-based behavioral treatment (FBT). METHODS: Neuroimaging and hormone assessments were conducted before and after 24-week FBT intervention in children with obesity (OB, n = 28), or children of healthy weight without intervention (HW, n = 17), all 9- to 11-year-old boys and girls. We evaluated meal-induced changes in neural activation to high- vs low-calorie food cues across appetite-processing brain regions and gut hormones. RESULTS: Among children with OB who underwent FBT, greater declines of BMI z-score were associated with lesser reductions after the FBT intervention in meal-induced changes in neural activation to high- vs low-calorie food cues across appetite-processing brain regions (P < 0.05), and the slope of relationship was significantly different compared with children of HW. In children with OB, less reduction in brain responses to a meal from before to after FBT was associated with greater meal-induced reduction in ghrelin and increased meal-induced stimulation in peptide YY and glucagon-like peptide-1 (all P < 0.05). CONCLUSION: In response to FBT, adaptations of central satiety responses and peripheral satiety-regulating hormones were noted. After weight loss, changes of peripheral hormone secretion support weight loss, but there was a weaker central satiety response. The findings suggest that even when peripheral satiety responses by gut hormones are intact, the central regulation of satiety is disturbed in children with OB who significantly improve their weight status during FBT, which could favor future weight regain.

Energy balance in hypothalamic obesity in response to treatment with a once-weekly GLP-1 receptor agonist.

BACKGROUND/OBJECTIVES: Hypothalamic obesity (HO) frequently occurs following suprasellar tumors from a combination of decreased energy expenditure and increased energy intake. Glucagon-like peptide-1 receptor agonist (GLP1RA) therapy is associated with increased satiety and energy expenditure. We hypothesized GLP1RA therapy in patients with HO would cause both lower energy intake and increased energy expenditure. SUBJECTS/METHODS: Forty-two patients aged 10-26 years (median 16 years) with HO with suprasellar tumors were randomized to GLP1RA (exenatide extended release once-weekly, ExQW, n = 23) or placebo (n = 19). Thirty seven (81%) patients completed the 36-week double-blind placebo-controlled trial. Total energy expenditure (TEE) was measured with doubly labeled water, physical activity was assessed with actigraphy, and intake was estimated with ad libitum buffet meal. Results are presented as adjusted mean between-group difference. RESULTS: As compared with treatment with placebo, treatment with ExQW was associated with decreased energy intake during a buffet meal (-1800 kJ (-430 kcal), 95% CI -3 184 to -418 kJ, p = 0.02). There were no significant differences in physical activity between groups. ExQW (vs. placebo) treatment was associated with a decrease in TEE (-695 kJ/day (-166 kcal/day), 95% CI -1 130 to -264 kJ/day, p < 0.01, adjusted for baseline TEE). The treatment effect was still significant after further adjustment for change in body composition (-372 kJ/day (-89 kcal/day), 95% CI -699 to -42 kJ/day, p = 0.04) or change in leptin (-695 kJ/day (-166 kcal/day), 95% CI -1 130 to -264 kJ/day, p < 0.01). This decrease in TEE occurred despite an increase in lean mass and fat mass (1.7 vs. 1.3 kg lean mass, p = 0.88 and 1.5 vs. 4.6 kg fat mass, p = 0.04, ExQW vs. placebo). CONCLUSIONS: Treatment with a GLP1RA was associated with a decrease in food intake but also a decrease in TEE that was disproportionate to change in body composition.

General and Food-Specific Impulsivity and Inhibition Related to Weight Management.

Background: Understanding child characteristics that relate to weight management treatment outcome could help identify opportunities for intervention innovation or tailoring. The limited evidence available is inconsistent regarding whether and which aspects of children's general or food-specific impulsivity and inhibition relate to treatment outcomes. Methods: Children with (n = 54) and without obesity (n = 22) were compared on various measures of impulsivity and inhibition. Children with obesity (n = 40) then completed family-based treatment for weight management. Analyses examined associations between baseline children's impulsivity and inhibition and child weight status change (BMI z-score) and between treatment-based changes in impulsivity and inhibition and weight status change, with and without adjustment by baseline functional magnetic resonance imaging-measured appetitive drive. Results: Children with obesity scored more poorly on some, but not all, measures of impulsivity and inhibition than children without obesity. Lower baseline general inhibition and greater parent-report of child impulsivity were associated (independently) with greater improvements in child weight status, with modest attenuation after appetite drive adjustment. Children improved task-based general inhibition during treatment. Improvements in general inhibition and snack food discounting were associated with better child weight outcomes, although adjusting for baseline values attenuated these associations. Conclusions: Children with obesity having greater initial impulsivity had better weight outcomes in treatment even after adjusting for initial appetitive drive. In contrast, improvements in task-based inhibition and food-related discounting during treatment were also related to better outcomes. Research is needed on innovative approaches to better address impulsivity and inhibition in children's weight management. Clinical Trial Registration number: NCT02484976.

A randomized double-blind placebo controlled pilot study of probiotics in adolescents with severe obesity.

PURPOSE: The purpose of the study is to assess the effect of probiotic supplementation on gut microbiota and insulin resistance in adolescents with severe obesity. METHODS: Through a randomized, double blind, placebo-controlled, 12-week pilot clinical trial, 15 adolescents with severe obesity received either an oral probiotic 'Visbiome®' (n = 8) or placebo (n = 7). Anthropometry, fasting glucose, insulin, hs-CRP and stool for microbiome and calprotectin were collected at baseline (week 0) and 12 weeks after intervention. RESULTS: Among completers (n = 4 in each of the two groups), mean change in fasting glucose was significantly lower in the probiotic group (0 ± 4 mg/dL) as compared to the placebo group (6.3 ± 1.7 mg/dL) (p = 0.028). Gut microbial Firmicutes to Bacteroidetes (F/B) ratio had a greater decline from week 0 to week 12 in the probiotic group (mean 17.7 ± 25.1 to 2.39 ± 2.0, respectively) but was not statistically significant (p = 0.06) as compared to in the placebo group (mean 12.8 ± 18.2 to 6.9 ± 5.61, respectively) (p = 0.89). Weight and BMI (mean ± SD) trended to remain stable in the treatment group (-1.07 ± 6.1 kg and -0.3 ± 2.2 kg/m2 respectively) as compared to the placebo group (3.9 ± 5.1 kg, 1.0 ± 1.6 kg/m2) but was not significant (p = 0.12 for weight and 0.38 for BMI). No significant change in the fasting insulin, HOMA-IR, or serum and stool inflammatory markers were noted between the two groups (p > 0.05). One participant in the treatment arm reported adverse effects of gastrointestinal intolerance. CONCLUSION: Probiotic therapy with Visbiome® may improve the fasting glucose and possibly decrease the gut microbial F/B ratio as compared to placebo in adolescents with severe obesity. Future larger studies are required to confirm these findings.U.S. Clinical Trial Registry number: NCT03109587. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-021-00855-7.

Robust Reductions of Body Weight and Food Intake by an Oxytocin Analog in Rats.

Background: Oxytocin is a hypothalamic neuropeptide that participates in the network of appetite regulation. Recently the oxytocin signaling pathway has emerged as an attractive target for treating obesity. However, the short half-life limits its development as a clinical therapeutic. Here we provide results from testing a long-lasting, potent and selective oxytocin analog ASK1476 on its efficacy to reduce food intake and body weight in comparison to the native oxytocin peptide. Methods: ASK1476 features two specific amino acid substitutions in positions 7 and 8 combined with a short polyethylene glycol spacer. Short time dose escalation experiments testing increasing doses of 3 days each were performed in diet-induced overweight (DIO) male rats assessing effects on body weight as well as changes in food intake. Furthermore, DIO rats were tested for changes in body weight, food intake, temperature, and locomotor activity over 28 days of treatment (oxytocin, ASK1476, or vehicle). Results: In dose escalation experiments, significant reductions in food intake relative to baseline were detected beginning with doses of 15 nmol/kg ASK1476 (-15.2 ± 2.3 kcal/d, p = 0.0017) and 20 nmol/kg oxytocin (-11.2.9 ± 2.4 kcal/d, p = 0.0106) with corresponding significant changes in body weight (ASK1476: -5.2 ± 0.8 g, p = 0.0016; oxytocin: -2.6 ± 0.7 g, p = 0.0326). In long-term experiments, there was no difference on body weight change between 120 nmol/kg/d ASK1476 (-71.4 ± 34.2 g, p = 0.039) and 600 nmol/kg/d oxytocin (-91.8 ± 32.2 g, p = 0.035) relative to vehicle (706.9 ± 28.3 g), indicating a stronger dose response for ASK1476. Likewise, both ASK1476 and oxytocin at these doses resulted in similar reductions in 28-day cumulative food intake (ASK1476: -562.7 ± 115.0 kcal, p = 0.0001; oxytocin: -557.1 ± 101.3 kcal, p = 0.0001) relative to vehicle treatment (2716 ± 75.4 kcal), while no effects were detected on locomotor activity or body temperature. Conclusion: This study provides proof-of-concept data demonstrating an oxytocin analog with extended in vivo stability and improved potency to reduce food intake and body weight in DIO animals which could mark a new avenue in anti-obesity drug interventions.

The link between obesity and puberty: what is new?

PURPOSE OF REVIEW: The objective of this review is to assess the most recent literature on pubertal trends in boys and girls as well as evaluate genetic, epigenetic, and environmental factors implicated in the timing of pubertal progression. RECENT FINDINGS: Recent studies confirm the previously described link between increased adiposity and earlier onset of puberty in girls, and more recent studies shed light onto the previously unclear situation in boys as a preponderance of recent longitudinal studies suggests that increased adiposity is linked with earlier pubertal timing also in boys. Discoveries of novel pathways highlights the complexity of pubertal development and suggest mechanistic links between nutrition, obesity, leptin, insulin resistance, and puberty. Furthermore, genetic and epigenetic variants can be linked to early puberty. Other factors, such as prenatal and postnatal environment, gut microbiota, and endocrine-disrupting chemicals have also been linked to both obesity and earlier puberty. SUMMARY: Understanding how the interactions of these factors contribute the relationship between obesity and early pubertal onset is crucial as early puberty has been linked with long-term consequences, such as short stature, earlier type 2 diabetes, cardiovascular disease, and poor psychological and behavioral outcomes.

MRI measures of hypothalamic injury are associated with glucagon-like peptide-1 receptor agonist treatment response in people with hypothalamic obesity.

AIM: To evaluate whether neuroimaging-delineated regions of hypothalamic injury are associated with a differential treatment response to a glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with hypothalamic obesity (HO). MATERIALS AND METHODS: We performed a prespecified secondary analysis of a randomized, multicentre, double-blind, placebo-controlled trial of people aged 10-25 years with hypothalamic injury and HO randomized to the GLP-1RA exenatide once-weekly (ExQW) or placebo for 36 weeks. Subjects underwent MRI prior to enrolment and the degree of hypothalamic damage was assessed using an integrative hypothalamic lesion score (HLS). Mammillary body (MB) damage was specifically determined. The main clinical endpoints were % change in body mass index (BMI) and change in % body fat. Nested ANCOVA models including a treatment × imaging measure interaction were compared using partial F-tests to assess whether the effect of ExQW treatment differed by severity of hypothalamic damage. RESULTS: Complete data were available in 35/42 randomized participants (placebo, n = 15; ExQW, n = 20). ExQW-treated patients with worse HLS or bilateral MB damage had greater reductions in % body fat at 36 weeks (interaction coefficient estimates for HLS: -0.9%, 95% CI -1.6% to -0.2%, p = .02; for MB damage: -7.4%, 95% CI -10.1% to -4.7%, p < .001, respectively) but not for BMI % change. Similarly, patients with more damaged and smaller MB cross-sectional areas had greater reductions in % body fat following ExQW (interaction coefficient estimate 0.3%, 95% CI 0.2%-0.4%, p < .001). CONCLUSIONS: In people with HO, greater hypothalamic damage as determined by MRI, in particular MB injury, is associated with greater reductions in adiposity following GLP-1RA treatment.

Design and Evaluation of Peptide Dual-Agonists of GLP-1 and NPY2 Receptors for Glucoregulation and Weight Loss with Mitigated Nausea and Emesis.

There is a critical unmet need for therapeutics to treat the epidemic of comorbidities associated with obesity and type 2 diabetes, ideally devoid of nausea/emesis. This study developed monomeric peptide agonists of glucagon-like peptide 1 receptor (GLP-1R) and neuropeptide Y2 receptor (Y2-R) based on exendin-4 (Ex-4) and PYY3-36. A novel peptide, GEP44, was obtained via in vitro receptor screens, insulin secretion in islets, stability assays, and in vivo rat and shrew studies of glucoregulation, weight loss, nausea, and emesis. GEP44 in lean and diet-induced obese rats produced greater reduction in body weight compared to Ex-4 without triggering nausea associated behavior. Studies in the shrew demonstrated a near absence of emesis for GEP44 in contrast to Ex-4. Collectively, these data demonstrate that targeting GLP-1R and Y2-R with chimeric single peptides offers a route to new glucoregulatory treatments that are well-tolerated and have improved weight loss when compared directly to Ex-4.

Pilot multi-site and reproducibility study of hypothalamic gliosis in children.

OBJECTIVE: Quantitative magnetic resonance imaging (MRI) evidence of mediobasal hypothalamic (MBH) gliosis positively correlates with body mass index (BMI) in adults. This has neither been well explored in children nor have other brain regions involved in appetitive processing been tested for evidence of gliosis. METHODS: Multi-site cross-sectional study in children to test for differences in quantitative T2 signal (measure of gliosis) by region and to assess relationships with age and BMI. Participants underwent brain MRI using the same equipment and protocol to quantify T2 relaxation time in six bilateral regions of interest (ROIs): putamen, caudate, ventral striatum, amygdala, hippocampus and MBH, and three control regions: white matter, motor cortex and dorsal hypothalamus. RESULTS: Thirty-one participants (61% female) were included in a combined sample from the University of Washington (N = 9) and John Hopkins University (N = 22). Mean age was 14 ± 3 years, and BMI z-score was 0.7 ± 1.1 (26% with obesity). No study site-related differences were seen in T2 relaxation time across all nine regions (chi2 (8): 9.46, P = .30). Regional differences in T2 relaxation time were present (P < .001). MBH presented longer T2 relaxation time, suggestive of gliosis, when compared to all regions (P < .001), including an intra-hypothalamic control. Physiological age-related declines in T2 relaxation times were found in grey matter ROIs, but not in the MBH (r = -0.14, P = .46). MBH was the only region with a positive correlation between T2 relaxation time and BMI z-score (r = 0.38, P = .03). CONCLUSIONS: In a multi-site study, pilot data suggest that quantitative MRI detected normal maturation-related brain variation as well as evidence that MBH gliosis is associated with increased adiposity in children.

A phase 3 randomized clinical trial using a once-weekly glucagon-like peptide-1 receptor agonist in adolescents and young adults with hypothalamic obesity.

AIM: To evaluate the efficacy, safety and tolerability of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in patients with hypothalamic obesity (HO). MATERIALS AND METHODS: A two-arm, randomized, multicentre, double-blind, placebo-controlled trial was conducted in 10- to 25-year-olds with hypothalamic injury following intracranial tumour and HO. Participants were randomized to once-weekly subcutaneous injections of a GLP-1 RA exenatide 2 mg (ExQW) or placebo for 36 weeks. The primary efficacy endpoint was 36-week % change in body mass index (BMI). Secondary outcomes included change in body composition (by dual energy x-ray absorptiometry). RESULTS: Forty-two participants were randomized to ExQW (n = 23) or placebo (n = 19). Participants were 5 ± 2 years (mean ± SD) postdiagnosis and development of HO (BMI 37.3 ± 7.1 kg/m2 ). In intention-to-treat analysis, the effect of 36-week ExQW vs. placebo on % Δ BMI was not significant (estimated treatment difference -1.7 ± 1.8%, 95% CI -4.1 to 0.6%, P = .40); however, total body fat mass was reduced (estimated treatment difference -3.1 ± 1.4 kg, 95% CI -5.7 to -0.4 kg, P = .02). There was a significant reduction in waist circumference (estimated effect of treatment -3.5 [95% CI -5.5 to -1.6] cm, P = .004). All patients treated with placebo increased % of adipose tissue, while 50% treated with ExQW had reductions (P < .001). Mean HbA1c, glucose tolerance and serum lipids did not change significantly with therapy. ExQW was well tolerated. The most frequent adverse events were transient gastrointestinal disturbances (ExQW vs. placebo: nausea 6/23 vs. 3/18, vomiting 4/23 vs. 4/18 and diarrhoea 7/23 vs. 3/18). CONCLUSIONS: GLP-1 RAs are a promising and safe treatment to improve or stabilize HO in children and young adults.

Connections Between Obesity and Puberty: Invited by Manuel Tena-Sempere, Cordoba.

The relationship between obesity and puberty remains controversial. Whereas cross-sectional and longitudinal studies show a clear shift toward earlier puberty in obese girls, the trend in obese boys remains less obvious. Overweight boys mature earlier whereas obese boys mature later compared to healthy weight boys. Newer epidemiologic studies attempt to address these knowledge gaps. This review provides a detailed overview of the recent literature regarding secular trends in pubertal onset and tempo, and the connection with obesity. Additionally, this review summarizes potential mediators that permit obesity to promote early puberty. Other factors such as socioeconomic status, in utero exposures, nutritional, and even endocrine disrupting chemicals can cause perturbation of both metabolism and the endocrine axis that can ultimately have effects on pubertal development.

Child neurobiology impacts success in family-based behavioral treatment for children with obesity.

BACKGROUND AND OBJECTIVES: Family-based behavioral treatment (FBT) is the recommended treatment for children with common obesity. However, there is a large variability in short- and long-term treatment response, and mechanisms for unsuccessful treatment outcomes are not fully understood. In this study, we tested if brain response to visual food cues among children with obesity before treatment predicted weight or behavioral outcomes during a 6-month behavioral weight management program and/or long-term relative weight maintenance over a 1-year follow-up period. SUBJECTS AND METHODS: Thirty-seven children with obesity (age 9-11 years, 62% male) who entered active FBT (attended two or more sessions) and had outcome data. Brain activation was assessed at pretreatment by functional magnetic resonance imaging across an a priori set of appetite-processing brain regions that included the ventral and dorsal striatum, mOFC, amygdala, substantia nigra/ventral tegmental area, and insula in response to viewing food images before and after a standardized meal. RESULTS: Children with more robust reductions in brain activation to high-calorie food cue images following a meal had greater declines in BMI z-score during FBT (r = 0.42; 95% CI: 0.09, 0.66; P = 0.02) and greater improvements in Healthy Eating Index scores (r = -0.41; 95% CI: -0.67, -0.06; P = 0.02). In whole-brain analyses, greater activation in the ventromedial prefrontal cortex, specifically by high-calorie food cues, was predictive of better treatment outcomes (whole-brain cluster corrected P = 0.02). There were no significant predictors of relative weight maintenance, and initial behavioral or hormonal measures did not predict FBT outcomes. CONCLUSIONS: Children's brain responses to a meal prior to obesity treatment were related to treatment-based weight outcomes, suggesting that neurophysiologic factors and appetitive drive, more so than initial hormone status or behavioral characteristics, limit intervention success.

Hypothalamic Obesity: Prologue and Promise.

Hypothalamic obesity (HO) frequently occurs following damage to the medial hypothalamic region, encompassing the arcuate nucleus, the paraventricular nucleus, the ventromedial nucleus, the dorsomedial nucleus, and the dorsal hypothalamic area, which are critically involved in the regulation of satiety and energy balance through neural and humoral connections. HO is most commonly described in the context of craniopharyngioma and its treatment, but it can also occur following other suprasellar tumors, radiation, trauma, or a surgical insult to the hypothalamus. A constellation of loss of satiety and a reduction of the metabolic rate, thermogenesis, and physical activity as well as increased vagal tone and hyperinsulinism with insulin and leptin resistance results in rapid weight gain due to a decreased energy expenditure and increased energy storage in adipose cells. To date, no viable long-term solution for HO has been found, due either to the requirement of intact hypothalamic pathways or to significant side effects. Newer therapeutic modalities focused on the unique pathophysiology of this condition offer potential for successful treatment. In this review, we describe the etiology of HO as well as past/current treatment approaches in the categories of hyperinsulinism, surgical approaches, and targeting energy expenditure/anorectic drugs. We conclude by providing an overview of the clinical trials currently underway.

Consuming glucose-sweetened, not fructose-sweetened, beverages increases fasting insulin in healthy humans.

Fructose-, compared to glucose-, sweetened beverages increase liver triglyceride content in the short-term, prior to weight gain. In secondary analyses of a randomized cross-over design study during which 24 healthy adults consumed 25% of their estimated energy requirement in the form of glucose-, fructose-, and high-fructose corn syrup-sweetened beverages in addition to an identical ad libitum diet for three periods of 8 days each, we investigated the hypothesis that fructose in sweetened beverages also triggers insulin resistance in the short term. Total energy intake, body weight, and fasting glucose did not differ among diet phases. However, there was a significant trend for higher fasting insulin (p = 0.042 for trend) and, among normal-weight participants, homeostasis model assessment index of insulin resistance (p = 0.034 for diet × adiposity interaction) according to the glucose content of the beverages. In conclusion, in contrast to our hypothesis, insulin resistance was increased with higher glucose vs. fructose content of the beverages in this short-term trial.

Central Nervous System and Peripheral Hormone Responses to a Meal in Children.

CONTEXT: Behavioral studies suggest that responses to food consumption are altered in children with obesity (OB). OBJECTIVE: To test central nervous system and peripheral hormone response by functional MRI and satiety-regulating hormone levels before and after a meal. DESIGN AND SETTING: Cross-sectional study comparing children with OB and children of healthy weight (HW) recruited from across the Puget Sound region of Washington. PARTICIPANTS: Children (9 to 11 years old; OB, n = 54; HW, n = 22), matched for age and sex. INTERVENTION AND OUTCOME MEASURES: Neural activation to images of high- and low-calorie food and objects was evaluated across a set of a priori appetite-processing regions that included the ventral and dorsal striatum, amygdala, substantia nigra/ventral tegmental area, insula, and medial orbitofrontal cortex. Premeal and postmeal hormones (insulin, peptide YY, glucagon-like peptide-1, active ghrelin) were measured. RESULTS: In response to a meal, average brain activation by high-calorie food cues vs objects in a priori regions was reduced after meals in children of HW (Z = -3.5, P < 0.0001), but not in children with OB (z = 0.28, P = 0.78) despite appropriate meal responses by gut hormones. Although premeal average brain activation by high-calorie food cues was lower in children with OB vs children of HW, postmeal activation was higher in children with OB (Z = -2.1, P = 0.04 and Z = 2.3, P = 0.02, respectively). An attenuated central response to a meal was associated with greater degree of insulin resistance. CONCLUSIONS: Our data suggest that children with OB exhibit an attenuated central, as opposed to gut hormone, response to a meal, which may predispose them to overconsumption of food or difficulty with weight loss.

Intraindividual Variation in Markers of Intestinal Permeability and Adipose Tissue Inflammation in Healthy Normal-Weight to Obese Adults.

BACKGROUND: Intestinal permeability and adipose tissue inflammation are considered mechanistic links in the relationship between diet, obesity, and chronic disease. However, methods to measure both are not well standardized, and the reliability of commonly used measures is not known. METHODS: We calculated the intraclass correlation coefficient (ICC) for several common measures of intestinal permeability and adipose tissue inflammation from a randomized clinical trial of cross-over design in which normal-weight (n = 12) or overweight/obese (n = 12) individuals each completed three 8-day dietary intervention periods. RESULTS: For biomarkers of intestinal permeability, plasma zonulin, and lipopolysaccharide-binding protein, ICCs were "excellent" (i.e., >0.9). The direct measure of intestinal permeability, the lactulose/mannitol test, exhibited "fair" reliability (ICC = 0.53). A wider range of ICCs (0.6-0.9), suggesting "good" to "excellent" reliability, were obtained for measures of adipose tissue expression of genes encoding major mediators of inflammation. Similarly, individual immune cell populations isolated from adipose tissue, expressed as a percentage of all CD45+ cells, also had "good" to "excellent" ICCs. However, when these populations were expressed as number of cells per gram of tissue, ICC values were "fair," falling below 0.6. CONCLUSIONS: Due to the repeated measures design, our study offered a unique opportunity to assess reliability of commonly used biomarkers of intestinal permeability and adipose tissue inflammation. Our findings suggest that these measures were generally highly reliable in the short-term. IMPACT: Along with other factors, particularly validity, the demonstrated reliabilities can help inform the choice of endpoints in studies of intestinal permeability and adipose tissue inflammation.