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.

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 Therapeutic Advances in Oncology

2021 ◽  
Vol 22 (4) ◽  
pp. 2008
Author(s):  
Jinsha Liu ◽  
Priyanka Pandya ◽  
Sepideh Afshar
Keyword(s):  
Small Molecules ◽  
New Technologies ◽  
Treatment Options ◽  
Current Treatment ◽  
Bispecific Antibodies ◽  
Gene Therapies ◽  
Therapeutic Modalities ◽  
The Past ◽  
Drug Conjugates ◽  
Novel Targets

Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment options in oncology, and an in-depth discussion of the therapeutics in the preclinical stage for the treatment of breast cancer, lung cancer, and multiple myeloma.

scholarly journals Knockout of inositol-requiring enzyme 1α in pro-opiomelanocortin neurons decreases fat mass via increasing energy expenditure

Open Biology ◽  
2016 ◽  
Vol 6 (8) ◽  
pp. 160131 ◽  
Author(s):  
Yuzhong Xiao ◽  
Tingting Xia ◽  
Junjie Yu ◽  
Yalan Deng ◽  
Hao Liu ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Liver Steatosis ◽  
Leptin Resistance ◽  
Hormone Production ◽  
Melanocyte Stimulating Hormone ◽  
Diet Induced Obesity ◽  
Brown Adipose

Although numerous functions of inositol-requiring enzyme 1α (IRE1α) have been identified, a role of IRE1α in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus is largely unknown. Here, we showed that mice lacking IRE1α specifically in POMC neurons (PIKO) are lean and resistant to high-fat diet-induced obesity and obesity-related insulin resistance, liver steatosis and leptin resistance. Furthermore, PIKO mice had higher energy expenditure, probably due to increased thermogenesis in brown adipose tissue. Additionally, α-melanocyte-stimulating hormone production was increased in the hypothalamus of PIKO mice. These results demonstrate that IRE1α in POMC neurons plays a critical role in the regulation of obesity and obesity-related metabolic disorders. Our results also suggest that IRE1α is not only an endoplasmic reticulum stress sensor, but also a new potential therapeutic target for obesity and obesity-related metabolic diseases.

Brain Tumors

2016 ◽  
pp. 11-24 ◽  
Author(s):  
Chikezie Eseonu ◽  
Jordina Rincon-Torroella ◽  
Alfredo Quiñones-Hinojosa
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Demyelinating Disease ◽  
Brain Lesion ◽  
Pituitary Tumors ◽  
Current Treatment ◽  
Preoperative Care ◽  
Adult Brain ◽  
Surgical Approaches

Brain tumor cases make up a significant part of the neurosurgery Oral Board Exam. A multitude of brain tumors exist and can be intraaxial or extraaxial. When considering a differential diagnosis for a brain lesion, infection, hematomas, infarctions, thrombosed aneurysms, inflammation, and demyelinating disease must be considered in addition to tumors. Common adult brain tumors consist of gliomas, meningiomas, metastases, and pituitary tumors. Management of brain tumors consists of understanding preoperative care, indications for surgery, surgical approaches, interpretation of preoperative and postoperative imaging, intraoperative and postoperative complications, and the role of adjuvant therapy, including chemotherapy and radiotherapy. Reviewing these essential points for the most common brain tumor cases and mastering the current treatment recommendations for common tumors will also be helpful for the boards.

Perfusions of the posterior hypothalamus of cats with various ions and saccharides: effects on body temperature

1978 ◽  
Vol 56 (4) ◽  
pp. 571-577 ◽  
Author(s):  
D. L. Jones ◽  
W. L. Veale ◽  
K. E. Cooper
Keyword(s):  
Body Temperature ◽  
Heat Loss ◽  
Posterior Hypothalamus ◽  
Body Temperatures ◽  
Vasomotor Tone ◽  
Hypothalamic Area ◽  
Hypothalamic Region ◽  
Energy Substrate ◽  
Available Energy ◽  
Perfusion Solution

Alterations of the ionic constituents of solutions perfused through the tissue of the posterior hypothalamic region in conscious cats elicited changes in body temperatures. Increasing the [Ca2+] to [Na+] ratio of the perfusion solution elicited falls in body temperature which were accompanied by changes in posture and vasomotor tone which assisted the heat loss. The magnitude of the fall was dependent on the ratio of [Ca2+] to [Na+] and was not related to the osmolarity of perfusion solution. The addition of dextrose to the perfusion solution attenuated or abolished the response produced by an increase in the [Ca2+] to [Na+] ratio. This dextrose effect could be attributed to its role as an energy substrate. These data are consistent with and extend previous suggestions that the set point for body temperature may be dependent on the inherent ratio of the ionic constituents of the posterior hypothalamic area. Further, they suggest that these ionically induced alterations can be overriden by increasing the available energy substrate.

scholarly journals Estradiol Prevents Fat Accumulation and Overcomes Leptin Resistance in Female High-Fat Diet Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (11) ◽  
pp. 4447-4460 ◽  
Author(s):  
Sara A. Litwak ◽  
Jenny L. Wilson ◽  
Weiyi Chen ◽  
Cecilia Garcia-Rudaz ◽  
Mohammad Khaksari ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Energy Expenditure ◽  
High Fat Diet ◽  
Fat Content ◽  
Leptin Resistance ◽  
Whole Body ◽  
High Fat ◽  
Fat Accumulation ◽  
The Metabolic Syndrome ◽  
Ovariectomized Mice

AbstractIn premenopausal and menopausal women in particular, suboptimal estrogens have been linked to the development of the metabolic syndrome as major contributors to fat accumulation. At the same time, estrogens have been described to have a role in regulating body metabolic status. We evaluated how endogenous or administered estrogens impact on the changes associated with high-fat diet (HFD) consumption in 2 different paradigms; ovarian-intact and in ovariectomized mice. When estradiol (E2) was cyclically administered to ovarian-intact HFD-fed mice for 12 weeks, animals gained significantly less weight than ovarian-intact vehicle controls (P < .01). This difference was mainly due to a reduced caloric intake but not to an increase in energy expenditure or locomotor activity. This E2 treatment regime to mice exposed to HFD was overall able to avoid the increase of visceral fat content to levels of those found in mice fed a regular chow diet. In the ovariectomized model, the main body weight and fat content reducing action of E2 was not only through decreasing food intake but also by increasing the whole-body energy expenditure, locomotor activity, and by inducing fat oxidation. Importantly, these animals became responsive to the anorexigenic effects of leptin in contrast to the vehicle-treated and the pair-fed control groups (P < .01). Further, in vitro hypothalamic secretion experiments revealed that treatment of obese mice with E2 is able to modulate the secretion of appetite-regulating neuropeptides; namely, E2 increased the secretion of the anorectic neuropeptide α-melanocyte-stimulating hormone and decreased the secretion of the orexigenic neuropetides neuropeptide Y and Agouti-related peptide. In conclusion, differences in response to E2 treatment of HFD-fed animals depend on their endogenous estrogenic status. Overall, E2 administration overcomes arcuate leptin resistance and partially prevents fat accumulation on these mice.

Weight change in patients with treatment of breast cancer.

2013 ◽  
Vol 31 (26_suppl) ◽  
pp. 127-127
Author(s):  
Lubna Chaudhary ◽  
Sijin Wen ◽  
Jie Xiao ◽  
Anne Swisher ◽  
Sobha Kurian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Menopausal Status ◽  
Distant Recurrence ◽  
Current Treatment ◽  
Stage Iii ◽  
Rank Test ◽  
Therapeutic Modalities ◽  
Treatment Regimens ◽  
Kaplan Meier ◽  
Significant Change

127 Background: Studies have shown that breast cancer (BC) treatment can increase weight (wt). Wt gain during chemotherapy is usually significant and maybe associated with poor survival. Role of current treatment regimens and wt gain is not reviewed. Methods: We retrospectively analyzed the mean percentage (%) wt change during the 1st year following BC diagnosis in 246 patients (pts) between Sept 2007 and Oct 2010. Kruskal-Wallis test and post-hoc pairwise comparisons were used to assess the influence of various factors including age, histology, stage, ER/PR/HER-2/neu status, menopausal status and types of therapeutic modalities received on the % wt change. Kaplan-Meier method with log-rank test was used to evaluate recurrence free survival (RFS). Local or distant recurrence and disease progression were events for RFS analysis and disease-free pts were censored at last follow-up. Results: Mean wt gain was 0.39% (±0.40) at 1 year from diagnosis of BC. Premenopausal status was the only factor associated with significant wt gain (+1.67% vs. -0.10% for postmenopausal pts; p=0.02). Stage ≥ III was associated with significant wt loss (-1.64% for III/IV vs. +0.85% for 0/I/II; p=0.02) and a lower RFS at 3yrs and 5yrs (p< 0.0001). Higher baseline wt (>90th percentile) did not have any significant impact on RFS at 3 years (0.84 vs. 0.91; p=0.19). There was no significant change in wt relative to other factors as shown in Table. Conclusions: Our study using current treatment regimens did not show any significant change in % wt with chemotherapy during the 1st year of BC diagnosis. Premenopausal status was the only factor associated with significant wt gain while stage ≥ III was associated with significant wt loss and lower RFS. [Table: see text]

scholarly journals Selective Inactivation of Socs3 in SF1 Neurons Improves Glucose Homeostasis without Affecting Body Weight

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5654-5661 ◽  
Author(s):  
Ren Zhang ◽  
Harveen Dhillon ◽  
Huali Yin ◽  
Akihiko Yoshimura ◽  
Bradford B. Lowell ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Glucose Homeostasis ◽  
Leptin Resistance ◽  
High Fat ◽  
Leptin Signaling ◽  
Leptin Sensitivity ◽  
High Fat Diets ◽  
Fat Diets

Suppressor of cytokine signaling 3 (Socs3) has been identified as a mediator of central leptin resistance, but the identity of specific neurons in which Socs3 acts to suppress leptin signaling remains elusive. The ventromedial hypothalamus (VMH) was recently shown to be an important site for leptin action because deleting leptin receptor within VMH neurons causes obesity. To examine the role of VMH Socs3 in leptin resistance and energy homeostasis, we generated mice lacking Socs3 specifically in neurons positive for steroidogenic factor 1 (SF1), which is expressed abundantly in the VMH. These mice had increased phosphorylation of signal transducer and activator of transcription-3 in VMH neurons, suggesting improved leptin signaling, and consistently, food intake and weight-reducing effects of exogenous leptin were enhanced. Furthermore, on either chow or high-fat diets, these mice had reduced food intake. Unexpectedly, energy expenditure was reduced as well. Mice lacking Socs3 in SF1 neurons, despite no change in body weight, had improved glucose homeostasis and were partially protected from hyperglycemia and hyperinsulinemia induced by high-fat diets. These results suggest that Socs3 in SF1 neurons negatively regulates leptin signaling and plays important roles in mediating leptin sensitivity, glucose homeostasis, and energy expenditure.

scholarly journals Novel Therapies for Relapsed and Refractory Neuroblastoma

Children ◽  
2018 ◽  
Vol 5 (11) ◽  
pp. 148 ◽  
Author(s):  
Peter Zage
Keyword(s):  
Clinical Trials ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Disease Relapse ◽  
Therapeutic Modalities ◽  
Treatment Regimens ◽  
Novel Treatment ◽  
Improved Outcomes ◽  
Outcomes For Children ◽  
Novel Treatment Strategies

While recent increases in our understanding of the biology of neuroblastoma have allowed for more precise risk stratification and improved outcomes for many patients, children with high-risk neuroblastoma continue to suffer from frequent disease relapse, and despite recent advances in our understanding of neuroblastoma pathogenesis, the outcomes for children with relapsed neuroblastoma remain poor. These children with relapsed neuroblastoma, therefore, continue to need novel treatment strategies based on a better understanding of neuroblastoma biology to improve outcomes. The discovery of new tumor targets and the development of novel antibody- and cell-mediated immunotherapy agents have led to a large number of clinical trials for children with relapsed neuroblastoma, and additional clinical trials using molecular and genetic tumor profiling to target tumor-specific aberrations are ongoing. Combinations of these new therapeutic modalities with current treatment regimens will likely be needed to improve the outcomes of children with relapsed and refractory neuroblastoma.

scholarly journals Endogenous VMH amylin signaling is required for full leptin signaling and protection from diet-induced obesity

2016 ◽  
Vol 310 (4) ◽  
pp. R355-R365 ◽  
Author(s):  
Ambrose A. Dunn-Meynell ◽  
Christelle Le Foll ◽  
Miranda D. Johnson ◽  
Thomas A. Lutz ◽  
Matthew R. Hayes ◽  
...  
Keyword(s):  
Ventromedial Hypothalamus ◽  
Tolerance Test ◽  
Leptin Resistance ◽  
Oral Glucose ◽  
Dorsomedial Nucleus ◽  
Adeno Associated Virus ◽  
Leptin Signaling ◽  
Insulin Resistant ◽  
Diet Induced Obesity ◽  
Hypothalamic Nuclei

Amylin enhances arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei leptin signaling and synergistically reduces food intake and body weight in selectively bred diet-induced obese (DIO) rats. Since DIO 125I-amylin dorsomedial nucleus-dorsomedial VMN binding was reduced, we postulated that this contributed to DIO ventromedial hypothalamus (VMH) leptin resistance, and that impairing VMH (ARC + VMN) calcitonin receptor (CTR)-mediated signaling by injecting adeno-associated virus (AAV) expressing a short hairpin portion of the CTR mRNA would predispose diet-resistant (DR) rats to obesity on high-fat (45%) diet (HFD). Depleting VMH CTR by 80–90% in 4-wk-old male DR rats reduced their ARC and VMN 125I-labeled leptin binding by 57 and 51%, respectively, and VMN leptin-induced phospho-signal transducer and activator of transcription 3-positive neurons by 59% vs. AAV control rats. After 6 wk on chow, VMH CTR-depleted DR rats ate and gained the equivalent amount of food and weight but had 18% heavier fat pads (relative to carcass weight), 144% higher leptin levels, and were insulin resistant compared with control AAV DR rats. After 6 wk more on HFD, VMH CTR-depleted DR rats ate the same amount but gained 28% more weight, had 60% more carcass fat, 254% higher leptin levels, and 132% higher insulin areas under the curve during an oral glucose tolerance test than control DR rats. Therefore, impairing endogenous VMH CTR-mediated signaling reduced leptin signaling and caused DR rats to become more obese and insulin resistant, both on chow and HFD. These results suggest that endogenous VMH amylin signaling is required for full leptin signaling and protection from HFD-induced obesity.

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