Pituitary hormones have long been thought solely to regulate single targets. Challenging this paradigm, we discovered that both anterior and posterior pituitary hormones, including FSH, had other functions in physiology. We have shown that FSH regulates skeletal integrity, and, more recently, find that the inhibition of FSH reduces body fat and induces thermogenic adipose tissue. A polyclonal antibody raised against a short, receptor-binding epitope of FSHβ was found not only to rescue bone loss post-ovariectomy, but also to display marked anti-obesity and pro-beiging actions. Questioning whether a single agent could be used to treat two medical conditions of public health importance -osteoporosis and obesity -we developed two further monoclonal antibodies, Hf2 and Mf4, against computationally defined receptor-binding epitopes of FSHβ. Hf2 has already been shown to reduce body weight, fat mass and cause beiging in mice on a high-fat diet. Here, we show that Hf2, which binds mouse Fsh in immunoprecipitation assays, also increases cortical thickness and trabecular bone volume, and microstructural parameters, in sham-operated and ovariectomized mice, noted on micro-computed tomography.This effect was largely recapitulated with Mf4, which inhibited bone resorption by osteoclasts and stimulated new bone formation by osteoblasts. These effects were exerted in the absence of alterations in serum estrogen in wild type mice. We also re-confirm the existence of Fshrs in bone by documenting the specific binding of fluorescently labeled FSH, FSH-CH, in vivo. Our study provides the framework for the future development of an FSH-based therapeutic that could potentially target both bone and fat. 3 SIGNIFICANCE STATEMENTWe have addressed the question whether osteoporosis and obesity, which often occur concurrently in postmenopausal women, can be targeted by a single agent. We have shown previously that the reproductive hormone FSH, the levels of which rise after menopause, regulates both body fat and bone mass. We now show that blocking FSH action using two purposefully designed epitope-specific antibodies protects against bone loss in mice. This positions both FSH antibodies as lead molecules for clinical development towards future use in people.
The lysosomal enzyme glucocerebrosidase-1 (GCase) catalyzes the cleavage of a major glycolipid glucosylceramide into glucose and ceramide. The absence of fully functional GCase leads to the accumulation of its lipid substrates in lysosomes, causing Gaucher disease, an autosomal recessive disorder that displays profound genotype–phenotype nonconcordance. More than 250 disease-causing mutations in GBA1, the gene encoding GCase, have been discovered, although only one of these, N370S, causes 70% of disease. Here, we have used a knowledge-based docking protocol that considers experimental data of protein–protein binding to generate a complex between GCase and its known facilitator protein saposin C (SAPC). Multiscale molecular-dynamics simulations were used to study lipid self-assembly, membrane insertion, and the dynamics of the interactions between different components of the complex. Deep learning was applied to propose a model that explains the mechanism of GCase activation, which requires SAPC. Notably, we find that conformational changes in the loops at the entrance of the substrate-binding site are stabilized by direct interactions with SAPC and that the loss of such interactions induced by N370S and another common mutation, L444P, result in destabilization of the complex and reduced GCase activation. Our findings provide an atomistic-level explanation for GCase activation and the precise mechanism through which N370S and L444P cause Gaucher disease.
Patients with history of intravenous drug abuse are noted to be at risk of several infections including HIV, endocarditis, and other opportunistic infections. We report the case of a patient with sustained Bacillus cereus bacteremia despite use of multiple antibiotic regimens during his inpatient stay. Our case highlights the importance of high suspicion for active drug use inside the hospital in such patients. This is important in order to minimize unnecessary diagnostic workup and provide adequate treatment and safe hospital stay for these patients.
Hypoglycemia is a rare complication of Hodgkin's disease. Several explanations have been postulated but the exact pathophysiology is not well understood. We are presenting a case of newly diagnosed Stage IV Hodgkin's disease that developed persistent and recurrent hypoglycemia despite giving glucagon, repeated 50% dextrose, and D5 and D10 continuous infusion. Hypoglycemia workup showed the C-peptide level to be low. Patient was suspected of having hypoglycemia related to lymphoma and was given a trial of prednisone which resolved the hypoglycemic episodes and made the patient euglycemic for the rest of his hospital stay. The presence of a substance that mimicked the effects of insulin was highly suspected. Several case reports strengthen the hypothesis of an insulin-like growth factor or antibodies secreted by the cancer cells causing hypoglycemia in Hodgkin's disease but none of them have been confirmed. Further investigation is warranted to more clearly define the pathophysiology of persistent hypoglycemia in patients with Hodgkin's disease.
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