Steroidogenic factor 1 (SF-1) neurons in the ventromedial hypothalamus effect on food intake

Obezite enerji alımı ve enerji harcanması arasındaki dengenin alım yönüne kayması ile gelişen önemli bir sağlık problemidir. Hipotalamustaki sinir ağlarının açlık ve tokluk hissini düzenlediği uzun zamandır bilinmektedir. Bu bölgede yer alan Ventromedyal hipotalamus (VMH) besin tüketiminde rol alan ve 'tokluk' merkezi olarak da bilinen bir çekirdektir. Enerji metabolizmasında ve glikoz dengesinden de sorumlu VMH'e yapılan lezyon çalışmaları ve bu çekirdekte bulunan nöral alt grupların genetik manipülasyonu hiperfajiyle karakterize obeziteye yol açtığı kanıtlansa da anlık iştah yönetiminde VMH nöronlarının işleyişi sinaptik düzeyde halen bilinmemektedir. Bu tezde hücre tipine özgün farmakogenetik teknikler kullanılarak VMH steroidojenik faktör 1 (SF-1) ifade eden nöronların anlık ve uzun süreli iştaha etkileri incelendi. Aç hayvanlarda SF-1 nöronlarının kemogenetik aktivasonu anlık besin tüketimini baskıladı (p<0.005). Tok hayvanlarda SF-1 nöronlarının kemogenetik inaktivasyonu sonucu anlık iştahta herhangi bir değişiklik gözlenmedi. Öte yandan, SF-1 nöronları apoptoz aracılı hücre ölümü ile ablasyonu sağlanarak, iştahta uzun süreli bir artış ve bununla birlikte ilerleyen kilo alımı görüldü (p<0.05). Bulgular, SF-1 ifade eden VMH nöronlarının iştahı ve vücut ağırlığını çok sıkı olmayan bir şekilde kontrol ettiğini göstermiştir.Obesity is an epidemic disease which is caused by the imbalance between energy intake and energy expenditure. It has been known that there are neuronal circuits in the hypothalamic region of the brain regulating appetite and body weight. Ventromedial hypothalamus (VMH) is one of the earliest identified 'satiety' centers and has long been implicated in feeding behavior. Despite the large body of literature suggesting that genetic or anatomical lesions to this region are sufficient to drive obese phenotype, precise role of electrical activity in VMH neurons for acute appetite regulation is not clear. In this thesis, cell type specific pharmacogenetic manipulation tools have been used to investigate role of VMH steroidogenic factor -1 (SF-1) neurons in short term regulation of appetite. Results indicate that while chemogenetic activation of SF-1 neurons inhibit food intake in food deprived mice (p<0.005), their inhibition does not result in significant food inhibiton in sated animals. In addition, specific ablation of VMHSF-1 neurons resulted in increased body weight and food intake over a period of several months (p<0.05). Collectively, these results suggest a permissive role for VMHSF-1 neuronal activity in short term regulation of food intake

Therapeutic utility of immunosuppressive TREM2+macrophages: An important step forward in potentiating the immune checkpoint inhibitors

In a recent article published in Cell, Molgora et al.1 reported that asubset of tumor-infiltrating macrophages with TREM2 expressioncreates an immunosuppressive microenvironment that promotestumor growth while suppressing anti-tumor immune responses.Targeting these TREM2+ macrophages via genetic ablation of thegene or specific antibodies against the protein reduces tumorgrowth in animal models; however, it further attenuates tumorgrowth when combined with immune checkpoint inhibitors (ICI)by promoting the expression of immunostimulatory molecules.Georgia Cancer Center startup fund ; American Cancer Society ; Bridge Fund by Augusta University Research Inc. ; Forbes Institute fund ; Evans County CARES fun

Dual function of HSP70 in cytoprotection of tumor cells and generation of immunosuppressive tumor microenvironment

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Adrenergic modulation of melanocortin pathway by hunger signals

Norepinephrine (NE) is a well-known appetite regulator, and the nor/adrenergic system is targeted by several anti-obesity drugs. To better understand the circuitry underlying adrenergic appetite control, here we investigated the paraventricular hypothalamic nucleus (PVN), a key brain region that integrates energy signals and receives dense nor/adrenergic input, using a mouse model. We found that PVN NE level increases with signals of energy deficit and decreases with food access. This pattern is recapitulated by the innervating catecholaminergic axon terminals originating from NTSTH-neurons. Optogenetic activation of rostral-NTSTH → PVN projection elicited strong motivation to eat comparable to overnight fasting whereas its inhibition attenuated both fasting-induced & hypoglycemic feeding. We found that NTSTH-axons functionally targeted PVNMC4R-neurons by predominantly inhibiting them, in part, through α1-AR mediated potentiation of GABA release from ARCAgRP presynaptic terminals. Furthermore, glucoprivation suppressed PVNMC4R activity, which was required for hypoglycemic feeding response. These results define an ascending nor/adrenergic circuit, NTSTH → PVNMC4R, that conveys peripheral hunger signals to melanocortin pathway.National Institutes of Healt