Hypothalamic obesity in children: pathophysiology to clinical management

2015 ◽  
Vol 28 (5-6) ◽  
Author(s):  
Belma Haliloglu ◽  
Abdullah Bereket
Keyword(s):  
Arcuate Nucleus ◽  
Severe Obesity ◽  
Genetic Diseases ◽  
Ventromedial Hypothalamus ◽  
Energy Regulation ◽  
Hypothalamic Obesity ◽  
Rapid Weight Gain ◽  
Hypothalamic Area ◽  
Diet And Exercise ◽  
Patients At Risk

AbstractHypothalamic obesity (HyOb) is a complex neuroendocrine disorder caused by damage to the hypothalamus, which results in disruption of energy regulation. The key hypothalamic areas of energy regulation are the ARC (arcuate nucleus), the VMH (ventromedial hypothalamus), the PVN (paraventriculer nuclei) and the LHA (lateral hypothalamic area). These pathways can be disrupted mechanically by hypothalamic tumors, neurosurgery, inflammatory disorders, radiotherapy and trauma or functionally as such seen in genetic diseases. Rapid weight gain and severe obesity are the most striking features of HyOb and caused by hyperphagia, reduced basal metabolic rate (BMR) and decreased physical activity. HyOb is usually unresponsive to diet and exercise. Although, GLP-1 and its anologs seem to be a new agent, there is still no curative treatment. Thus, prevention is of prime importance and the clinicians should be alert and vigilant in patients at risk for development of HyOb.

scholarly journals Hypothalamic Obesity: Prologue and Promise

2019 ◽  
Vol 91 (2) ◽  
pp. 128-136 ◽  
Author(s):  
M. Jennifer Abuzzahab ◽  
Christian L. Roth ◽  
Ashley H. Shoemaker
Keyword(s):  
Energy Expenditure ◽  
Current Treatment ◽  
Leptin Resistance ◽  
Surgical Approaches ◽  
Dorsomedial Nucleus ◽  
Hypothalamic Obesity ◽  
Rapid Weight Gain ◽  
Hypothalamic Area ◽  
Hypothalamic Region ◽  
Therapeutic Modalities

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.

scholarly journals Impact of weight loss achieved through a multidisciplinary intervention on appetite in patients with severe obesity

2018 ◽  
Vol 315 (1) ◽  
pp. E91-E98 ◽  
Author(s):  
S. R. Coutinho ◽  
J. F. Rehfeld ◽  
J. J. Holst ◽  
B. Kulseng ◽  
C. Martins
Keyword(s):  
Weight Loss ◽  
Severe Obesity ◽  
Peptide Yy ◽  
Plasma Concentrations ◽  
Cardiovascular Fitness ◽  
Ghrelin Concentration ◽  
Time Points ◽  
Diet And Exercise ◽  
The Impact

The impact of lifestyle-induced weight loss (WL) on appetite in patients with obesity remains controversial. This study aimed to assess the short- and long-term impact of WL achieved by diet and exercise on appetite in patients with obesity. Thirty-five (22 females) adults with severe obesity (body mass index: 42.5 ± 5.0 kg/m2) underwent a 2-yr WL program focusing on diet and exercise. Body weight (BW), cardiovascular fitness (V̇o2max), appetite feelings, and plasma concentrations of insulin, active ghrelin (AG), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK), in the fasting and postprandial states, were measured at baseline (B), week 4 (W4), and 1 and 2 yr (and average values for all fasting and postprandial time points computed). BW was significantly reduced and V̇o2max(ml·kg−1·min−1) increased at all time points compared with B (3.5, 8.1, and 8.4% WL and 7, 11, and 8% increase at W4 and 1 and 2 yr, respectively). Basal hunger and average hunger and desire to eat were significantly increased at 1 and 2 yr. Basal fullness was significantly increased at W4, and average ratings were reduced at 1 yr. Average AG and PYY were significantly increased, and insulin was reduced, at all time points compared with B. Average GLP-1 was reduced at W4, and CCK was increased at 2 yr. After lifestyle-induced WL, patients with severe obesity will, therefore, have to deal with increased hunger in the long term. In conclusion, sustained WL at 2 yr achieved with diet and exercise is associated with increased hunger feelings and ghrelin concentration but also increased postprandial concentrations of satiety hormones.

The hyperthermic effect of central cholecystokinin is mediated by the cyclooxygenase-2 pathway

2021 ◽  
Author(s):  
Patrik Keringer ◽  
Nora Furedi ◽  
Balazs Gaszner ◽  
Alexandra Miko ◽  
Eszter Pakai ◽  
...  
Keyword(s):  
Body Temperature ◽  
Enzyme Inhibitor ◽  
Core Body Temperature ◽  
Ventromedial Hypothalamus ◽  
Neuronal Activation ◽  
Hypothalamic Area ◽  
Induced Hyperthermia ◽  
Male Wistar Rats ◽  
Cox 2 ◽  
Fever Response

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam or etoricoxib (10 mg/kg for both) and, 30 minutes later, treated with icv CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ~0.4°C from 10 min post-infusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ~70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ~50% in both); all these changes were all completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg; icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways, and that the activation of COX-2 is required for the development of this response.

scholarly journals Arcuate nucleus injection of an anti-insulin affibody prevents the sympathetic response to insulin

2013 ◽  
Vol 304 (11) ◽  
pp. H1538-H1546 ◽  
Author(s):  
Brittany S. Luckett ◽  
Jennifer L. Frielle ◽  
Lawrence Wolfgang ◽  
Sean D. Stocker
Keyword(s):  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Arcuate Nucleus ◽  
Insulin Receptors ◽  
Ventromedial Hypothalamus ◽  
Intracerebroventricular Injection ◽  
Sprague Dawley ◽  
Nerve Activity ◽  
Sympathetic Response ◽  
Sprague Dawley Rats

Accumulating evidence suggests that insulin acts within the hypothalamus to alter sympathetic nerve activity (SNA) and baroreflex function. Although insulin receptors are widely expressed across the hypothalamus, recent evidence suggests that neurons of the arcuate nucleus (ARC) play an important role in the sympathoexcitatory response to insulin. The purpose of the present study was to determine whether circulating insulin acts directly in the ARC to elevate SNA. In anesthetized male Sprague-Dawley rats (275–425 g), the action of insulin was neutralized by microinjection of an anti-insulin affibody (1 ng/40 nl). To verify the efficacy of the affibody, ARC pretreatment with injection of the anti-insulin affibody completely prevented the increase in lumbar SNA produced by ARC injection of insulin. Next, ARC pretreatment with the anti-insulin affibody attenuated the lumbar sympathoexcitatory response to intracerebroventricular injection of insulin. Third, a hyperinsulinemic-euglycemic clamp increased lumbar, but not renal, SNA in animals that received ARC injection of a control affibody. However, this sympathoexcitatory response was absent in animals pretreated with the anti-insulin affibody in the ARC. Injection of the anti-insulin affibody in the adjacent ventromedial hypothalamus did not alter the sympathoexcitatory response to insulin. The ability of the anti-insulin affibody to prevent the sympathetic effects of insulin cannot be attributed to a general inactivation or nonspecific effect on ARC neurons as the affibody did not alter the sympathoexcitatory response to ARC disinhibition by gabazine. Collectively, these findings suggest that circulating insulin acts within the ARC to increase SNA.

scholarly journals Region-Specific Reduction in Leptin-Induced Phosphorylation of Signal Transducer and Activator of Transcription-3 (STAT3) in the Rat Hypothalamus Is Associated with Leptin Resistance during Pregnancy

Endocrinology ◽  
2004 ◽  
Vol 145 (8) ◽  
pp. 3704-3711 ◽  
Author(s):  
S. R. Ladyman ◽  
D. R. Grattan
Keyword(s):  
Food Intake ◽  
Arcuate Nucleus ◽  
Ventromedial Hypothalamus ◽  
Leptin Resistance ◽  
Signal Transducer ◽  
Pregnant Rats ◽  
Hypothalamic Nuclei ◽  
Stat3 Phosphorylation ◽  
Vehicle Treatment ◽  
Plasma Leptin

Abstract Leptin concentrations increase during pregnancy, but this does not prevent the pregnancy-induced increase in food intake, suggesting a state of leptin resistance. This study investigated the response to intracerebroventricular leptin administration in pregnant rats. After fasting, nonpregnant, d-7 and d-14 pregnant rats received leptin (4 μg) or vehicle, then food intake was measured. Serial blood samples were collected in another group of rats to determine plasma leptin concentrations. Further groups of d-14 pregnant and nonpregnant rats were killed after leptin or vehicle treatment, and brains were collected. Hypothalamic nuclei were microdissected, and levels of signal transducer and activator of transcription (STAT)3 phosphorylation were measured using Western blot analysis. Fasting decreased leptin concentrations in both pregnant and nonpregnant rats. Leptin treatment significantly reduced food intake in nonpregnant and d-7 pregnant rats but not in d-14 pregnant rats. In addition, there was no postfasting hyperphagic response in the pregnant rats. In the pregnant rats, leptin-induced STAT3 phosphorylation was suppressed in the arcuate nucleus and, to a lesser extent, in the ventromedial hypothalamus (VMH), compared with nonpregnant rats. Unstimulated STAT3 levels were also decreased in the VMH during pregnancy. Leptin-induced phosphorylation of STAT3 in the dorsomedial and lateral hypothalamus was not different between pregnant and nonpregnant rats. These data indicate that pregnant rats become resistant to the satiety action of leptin. Furthermore, leptin-induced activation of the STAT3 is impaired during pregnancy, specifically in the arcuate nucleus and VMH. These data support the hypothesis that pregnancy is a state of hypothalamic leptin resistance.

Prior vagotomy blocks VMH obesity in pair-fed rats

1981 ◽  
Vol 240 (5) ◽  
pp. E573-E583 ◽  
Author(s):  
J. E. Cox ◽  
T. L. Powley
Keyword(s):  
Food Intake ◽  
Cell Loss ◽  
Ventromedial Hypothalamus ◽  
Motor Nucleus ◽  
Previous Suggestion ◽  
Hypothalamic Obesity ◽  
Dorsal Motor Nucleus ◽  
Gastric Contents ◽  
Feeding Regimen ◽  
Protein Output

Previously vagotomized, ventromedial hypothalamus (VMH)-lesioned rats and sham-lesioned controls were maintained on an intragastric pair-feeding regimen in which nonvagotomized VMH rats deposit excessive fat. Hypothalamic lesions were produced after 6 days of adaptation to pair feeding, and the experiment continued for 30 days postlesion. Extent of vagotomy was determined with a multiple-regression procedure with cell loss in the dorsal motor nucleus of the vagus, fasting gastric contents, and basal pancreatic protein output as predictor variables. The correlation was 0.95 between this set of indexes and the adequacy of a vagotomy for preventing hypothalamic obesity. Thus, radical vagotomies precluded the typical accumulation of significantly increased levels of carcass fat in lesioned animals (16.3 vs. 14.0% for controls). VMH rats with less extensive transections accumulated substantially more fat (25.9%). This outcome suggests that vagotomy produces a specific blockade of lesion-produced disturbances in metabolism leading to obesity. It fails to support a previous suggestion that vagal section blocks VMH obesity merely as a nonspecific surgical restriction of food intake because vagotomy was effective even though its effects on food intake could not operate.

scholarly journals Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin

2010 ◽  
Vol 108 (1) ◽  
pp. 355-360 ◽  
Author(s):  
Masoud Ghamari-Langroudi ◽  
Dollada Srisai ◽  
Roger D. Cone
Keyword(s):  
Paraventricular Nucleus ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Ventromedial Hypothalamus ◽  
Postsynaptic Membrane ◽  
Firing Frequency ◽  
Dependent Manner ◽  
Primary Control ◽  
Regulation Of Activity

Melanocortin-4 receptor (MC4R) is critical for energy homeostasis, and the paraventricular nucleus of the hypothalamus (PVN) is a key site of MC4R action. Most studies suggest that leptin regulates PVN neurons indirectly, by binding to receptors in the arcuate nucleus or ventromedial hypothalamus and regulating release of products like α-melanocyte-stimulating hormone (α-MSH), neuropeptide Y (NPY), glutamate, and GABA from first-order neurons onto the MC4R PVN cells. Here, we investigate mechanisms underlying regulation of activity of these neurons under various metabolic states by using hypothalamic slices from a transgenic MC4R-GFP mouse to record directly from MC4R neurons. First, we show that in vivo leptin levels regulate the tonic firing rate of second-order MC4R PVN neurons, with fasting increasing firing frequency in a leptin-dependent manner. We also show that, although leptin inhibits these neurons directly at the postsynaptic membrane, α-MSH and NPY potently stimulate and inhibit the cells, respectively. Thus, in contrast with the conventional model of leptin action, the primary control of MC4R PVN neurons is unlikely to be mediated by leptin action on arcuate NPY/agouti-related protein and proopiomelanocortin neurons. We also show that the activity of MC4R PVN neurons is controlled by the constitutive activity of the MC4R and that expression of the receptor mRNA and α-MSH sensitivity are both stimulated by leptin. Thus, leptin acts multinodally on arcuate nucleus/PVN circuits to regulate energy homeostasis, with prominent mechanisms involving direct control of both membrane conductances and gene expression in the MC4R PVN neuron.

The effect of fetal hypothalamus grafts on weight gain resulting from lesions of the ventromedial hypothalamus

1988 ◽  
Vol 68 (1) ◽  
pp. 112-116 ◽  
Author(s):  
Robert K. Erickson ◽  
Frederick D. Brown ◽  
Keith L. Schaible ◽  
Robert L. Wollmann
Keyword(s):  
Weight Gain ◽  
Treatment Group ◽  
Third Ventricle ◽  
Fetal Brain ◽  
Ventromedial Hypothalamus ◽  
Daily Weight Gain ◽  
Control Group ◽  
Adult Rats ◽  
Rapid Weight Gain ◽  
Content Type

✓ Bilateral ventromedial hypothalamic lesions in female adult rats which resulted in hyperphagia and rapid weight gain were followed by placement of fetal brain tissue in the anterior third ventricle. The treatment group received fetal hypothalamus grafts, and fetal cortical tissue of identical age was grafted into the control group. A significant reduction in average daily weight gain was noted from 4 to 12 weeks following transplantation in the treatment group. At 12 weeks posttransplantation, the animals were sacrificed for histological analysis. Examination of the hypothalamus grafts revealed neurons, ependymal clusters, and axonal processes which appeared to infiltrate the surrounding hypothalamic parenchyma.

scholarly journals Hyperphagia in children with craniopharyngioma is associated with hyperleptinaemia and a failure in the downregulation of appetite

1998 ◽  
Vol 138 (1) ◽  
pp. 89-91 ◽  
Author(s):  
C Roth ◽  
B Wilken ◽  
F Hanefeld ◽  
W Schroter ◽  
U Leonhardt
Keyword(s):  
Body Mass Index ◽  
Severe Obesity ◽  
Elevated Serum ◽  
Feedback Mechanism ◽  
Normal Serum ◽  
Hypothalamic Obesity ◽  
Serum Leptin ◽  
Leptin Receptors ◽  
Neurosurgical Treatment ◽  
Normal Controls

Patients with craniopharyngioma frequently suffer from severe obesity. Leptin induces an inhibition of appetite via hypothalamic receptors. This study was undertaken to investigate whether a relationship exists between serum leptin levels and pituitary/hypothalamic lesions in craniopharyngioma patients. Serum leptin levels were evaluated by RIA in 14 patients (age 7-21 years; 7 females, 7 males) after they had undergone neurosurgical treatment for craniopharyngioma. Normal controls had a positive correlation between leptin levels and body mass index (BMI) with higher levels in the females than in the males. Significantly elevated leptin levels with respect to BMI were found in 11 craniopharyngioma patients who had been affected by a suprasellar tumour, whereas 3 patients with an intrasellar tumour had lower, almost normal serum leptin levels. Our data suggest that craniopharyngioma patients develop hypothalamic obesity because their hypothalamic structures are insensitive to endogenous leptin. The elevated serum leptin concentrations found only in patients with a suprasellar tumour may be explained by a disturbed feedback mechanism from the hypothalamic leptin receptors to the adipose tissue.

scholarly journals TrkB-expressing paraventricular hypothalamic neurons suppress appetite through multiple neurocircuits

2019 ◽  
Author(s):  
Juan Ji An ◽  
Clint E. Kinney ◽  
Guey-Ying Liao ◽  
Eric J. Kremer ◽  
Baoji Xu
Keyword(s):  
Energy Balance ◽  
Severe Obesity ◽  
Ventromedial Hypothalamus ◽  
Brain Regions ◽  
Neuronal Population ◽  
Parabrachial Nucleus ◽  
Trkb Receptor ◽  
Lateral Parabrachial Nucleus ◽  
Its Gene ◽  
Neural Substrate

ABSTRACTThe TrkB receptor is critical for the control of energy balance, as mutations in its gene (NTRK2) lead to hyperphagia and severe obesity in humans and mice. The main neural substrate mediating the appetite-suppressing activity of TrkB, however, remains unknown. Here, we demonstrate that selective Ntrk2 deletion within the paraventricular hypothalamus (PVH) leads to severe hyperphagic obesity. Furthermore, chemogenetic activation or inhibition of TrkB-expressing PVH (PVHTrkB) neurons suppresses or increases food intake, respectively. PVHTrkB neurons project to multiple brain regions, including the ventromedial hypothalamus (VMH) and the lateral parabrachial nucleus (LPBN). We found that PVHTrkB neurons projecting to LPBN are distinct from those projecting to VMH, yet Ntrk2 deletion in PVH neurons projecting to either VMH or LPBN results in hyperphagia and obesity. Therefore, TrkB signaling is a key regulator of a previously uncharacterized and heterogenous neuronal population within the PVH that impinges upon multiple circuits to govern appetite.

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