HuR controls glutaminase RNA metabolism.

Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer.

Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear.

Reduction of oxytocin-containing neurons and enhanced glymphatic activity in the hypothalamic paraventricular nucleus of patients with type 2 diabetes mellitus.

Evidence from animal experiments has shown that the hypothalamic paraventricular nucleus (PVN) plays a key role in regulating body weight and blood glucose levels. However, it is unclear whether neuron populations in the human PVN are involved in the development of type 2 diabetes mellitus (T2DM). To address this, we investigated the neuronal and glial populations in the PVN of 26 T2DM patients and 20 matched controls.

Tissue-specific metabolic profile drives iNKT cell function during obesity and liver injury.

Invariant natural killer T (iNKT) cells are a distinct population of lymphocytes characterized by their reactivity to glycolipids presented by CD1d. iNKT cells are found throughout the body, and little is known about their tissue-specific metabolic regulation. Here, we show that splenic and hepatic iNKT cells are metabolically comparable and rely on glycolytic metabolism to support their activation.

Loss of Microglial Insulin Receptor Leads to Sex-Dependent Metabolic Disorders in Obese Mice.

Obesity and type 2 diabetes mellitus (T2DM) are highly prevalent disorders, associated with insulin resistance and chronic inflammation. The brain is key for energy homeostasis and contains many insulin receptors. Microglia, the resident brain immune cells, are known to express insulin receptors (InsR) and to be activated by a hypercaloric environment.

Hypothalamic neuropeptides and neurocircuitries in Prader Willi syndrome.

Prader-Willi Syndrome (PWS) is a rare and incurable congenital neurodevelopmental disorder, resulting from the absence of expression of a group of genes on the paternally acquired chromosome 15q11-q13. Phenotypical characteristics of PWS include infantile hypotonia, short stature, incomplete pubertal development, hyperphagia and morbid obesity. Hypothalamic dysfunction in controlling body weight and food intake is a hallmark of PWS.

Mapping of Microglial Brain Region, Sex and Age Heterogeneity in Obesity.

The prevalence of obesity has increased rapidly in recent years and has put a huge burden on healthcare worldwide. Obesity is associated with an increased risk for many comorbidities, such as cardiovascular diseases, type 2 diabetes and hypertension. The hypothalamus is a key brain region involved in the regulation of food intake and energy expenditure.

Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity.

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD).

Lipid Droplets Accumulate in the Hypothalamus of Mice and Humans with and without Metabolic Diseases.

Background: In peripheral tissues, the lipid droplet (LD) organelle links lipid metabolism, inflammation, and insulin resistance. Little is known about the brain LDs.

Objectives: We hypothesized that hypothalamic LDs would be altered in metabolic diseases.

Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells.

Triple-negative breast cancers (TNBCs) lack progesterone and estrogen receptors and do not have amplified human epidermal growth factor receptor 2, the main therapeutic targets for managing breast cancer. TNBCs have an altered metabolism, including an increased Warburg effect and glutamine dependence, making the glutaminase inhibitor CB-839 therapeutically promising for this tumor type. Accordingly, CB-839 is currently in phase I/II clinical trials.

Castration-induced prostate epithelial cell apoptosis results from targeted oxidative stress attack of M1 -macrophages.

Prostate development and function are regulated by androgens. Epithelial cell apoptosis in response to androgen deprivation is caspase-9-dependent and peaks at Day 3 after castration. However, isolated epithelial cells survive in the absence of androgens.

Association between tumor-infiltrating lymphocytes and sentinel lymph node positivity in thin melanoma.

Background: Sentinel lymph node biopsy in thin invasive primary cutaneous melanoma (up to 1mm thick) is a controversial subject. The presence of tumor-infiltrating lymphocytes could be a factor to be considered in the decision to perform this procedure.

Objective: To evaluate the association between the presence of tumor-infiltrating lymphocytes and lymph node metastases caused by thin primary cutaneous melanoma.

The partial inhibition of hypothalamic IRX3 exacerbates obesity.

Background: The Iroquois homeobox 3 (Irx3) gene has been identified as a functional long-range target of obesity-associated variants within the fat mass and obesity-associated protein (FTO) gene. It is highly expressed in the hypothalamus, and both whole-body knockout and hypothalamic restricted abrogation of its expression results in a lean phenotype, which is mostly explained by the resulting increased energy expenditure in the brown adipose tissue. Because of its potential implication in the pathogenesis of obesity, we evaluated the hypothalamic cell distribution of Irx3 and the outcomes of inhibiting its expression in a rodent model of diet-induced obesity.

Downregulation of HIF complex in the hypothalamus exacerbates diet-induced obesity.

Hypothalamic hypoxia-inducible factor-1 (HIF-1) can regulate whole-body energy homeostasis in response to changes in blood glucose, suggesting that it acts as a sensor for systemic energy stores. Here, we hypothesized that hypothalamic HIF-1 could be affected by diet-induced obesity (DIO). We used eight-week old, male C57Bl6 mice, fed normal chow diet or with high fat diet for 1, 3, 7, 14 and 28 days.

Mitoimmunity-when mitochondria dictates macrophage function.

In the past decade, several reports have appointed the importance of mitochondria in the immune response. Our understanding of mitochondria evolved from a simple supplier of energy into a platform necessary for immunorregulation. Proinflammatory responses are associated with enhanced glycolytic activity and breakdown of the TCA cycle.

Resolvin RvD2 reduces hypothalamic inflammation and rescues mice from diet-induced obesity.

Background: Diet-induced hypothalamic inflammation is an important mechanism leading to dysfunction of neurons involved in controlling body mass. Studies have shown that polyunsaturated fats can reduce hypothalamic inflammation. Here, we evaluated the presence and function of RvD2, a resolvin produced from docosahexaenoic acid, in the hypothalamus of mice.