Deficiency of ER Ca2+ sensor STIM1 in AgRP neurons confers protection against dietary obesity.

Store-operated calcium entry (SOCE) is pivotal in maintaining intracellular Ca2+ level and cell function; however, its role in obesity development remains largely unknown. Here, we show that the stromal interaction molecule 1 (Stim1), an endoplasmic reticulum (ER) Ca2+ sensor for SOCE, is critically involved in obesity development. Pharmacological blockade of SOCE in the brain, or disruption of Stim1 in hypothalamic agouti-related peptide (AgRP)-producing neurons (ASKO), significantly ameliorates dietary obesity and its associated metabolic disorders. Conversely, constitutive activation of Stim1 in AgRP neurons leads to an obesity-like phenotype. We show that the blockade of SOCE suppresses general translation in neuronal cells via the 2',5'-oligoadenylate synthetase 3 (Oas3)-RNase L signaling. While Oas3 overexpression in AgRP neurons protects mice against dietary obesity, deactivation of RNase L in these neurons significantly abolishes the effect of ASKO. These findings highlight an important role of Stim1 and SOCE in the development of obesity.

Stimulation of hypothalamic oxytocin neurons suppresses colorectal cancer progression in mice.

Emerging evidence suggests that the nervous system is involved in tumor development in the periphery, however, the role of the central nervous system remains largely unknown. Here, by combining genetic, chemogenetic, pharmacological, and electrophysiological approaches, we show that hypothalamic oxytocin (Oxt)-producing neurons modulate colitis-associated cancer (CAC) progression in mice. Depletion or activation of Oxt neurons could augment or suppress CAC progression. Importantly, brain treatment with celastrol, a pentacyclic triterpenoid, excites Oxt neurons and inhibits CAC progression, and this anti-tumor effect was significantly attenuated in Oxt neuron-lesioned mice. Furthermore, brain treatment with celastrol suppresses sympathetic neuronal activity in the celiac-superior mesenteric ganglion (CG-SMG), and activation of ß2 adrenergic receptor abolishes the anti-tumor effect of Oxt neuron activation or centrally administered celastrol. Taken together, these findings demonstrate that hypothalamic Oxt neurons regulate CAC progression by modulating the neuronal activity in the CG-SMG. Stimulation of Oxt neurons using chemicals, for example, celastrol, might be a novel strategy for colorectal cancer treatment.

Colorectal (or 'bowel') cancer killed nearly a million people in 2018 alone: it is, in fact, the second leading cause of cancer death globally. Lifestyle factors and inflammatory bowel conditions such as chronic colitis can heighten the risk of developing the disease. However, research has also linked to the development of colorectal tumours to stress, anxiety and depression. This 'brain-gut' connection is particularly less-well understood. One brain region of interest is the hypothalamus, an almond-sized area which helps to regulate mood and bodily processes using chemical messengers that act on various cells in the body. For instance, Oxt neurons in the hypothalamus produce the hormone oxytocin which regulates emotional and social behaviours. These cells play an important role in modulating anxiety, stress and depression. To investigate whether they could also influence the growth of colorectal tumours, Pan et al. used various approaches to manipulate the activity of Oxt neurons in mice with colitis-associated cancer. Disrupting the Oxt neurons in these animals increased anxiety-like behaviours and promoted tumour growth. Stimulating these cells, on the other hand, suppressed cancer progression. Further experiments also showed that treating the mice with celastrol, a plant extract which can act on the hypothalamus, stimulated Oxt neurons and reduced tumour growth. In particular, the compound worked by acting on a nerve structure in the abdomen which relays messages to the gut. These preliminary findings suggest that the hypothalamus and its Oxt-producing neurons may influence the progression of colorectal cancer in mice by regulating the activity of an abdominal 'hub' of the nervous system. Modulating the activity of Oxt-producing neurons could therefore be a potential avenue for treatment.

Hypothalamic extended synaptotagmin-3 contributes to the development of dietary obesity and related metabolic disorders.

The C2 domain containing protein extended synaptotagmin (E-Syt) plays important roles in both lipid homeostasis and the intracellular signaling; however, its role in physiology remains largely unknown. Here, we show that hypothalamic E-Syt3 plays a critical role in diet-induced obesity (DIO). E-Syt3 is characteristically expressed in the hypothalamic nuclei. Whole-body or proopiomelanocortin (POMC) neuron-specific ablation of E-Syt3 ameliorated DIO and related comorbidities, including glucose intolerance and dyslipidemia. Conversely, overexpression of E-Syt3 in the arcuate nucleus moderately promoted food intake and impaired energy expenditure, leading to increased weight gain. Mechanistically, E-Syt3 ablation led to increased processing of POMC to α-melanocyte-stimulating hormone (α-MSH), increased activities of protein kinase C and activator protein-1, and enhanced expression of prohormone convertases. These findings reveal a previously unappreciated role for hypothalamic E-Syt3 in DIO and related metabolic disorders.

Caffeine inhibits hypothalamic A1R to excite oxytocin neuron and ameliorate dietary obesity in mice.

Caffeine, an antagonist of the adenosine receptor A1R, is used as a dietary supplement to reduce body weight, although the underlying mechanism is unclear. Here, we report that adenosine level in the cerebrospinal fluid, and hypothalamic expression of A1R, are increased in the diet-induced obesity (DIO) mouse. We find that mice with overexpression of A1R in the neurons of paraventricular nucleus (PVN) of the hypothalamus are hyperphagic, have glucose intolerance and high body weight. Central or peripheral administration of caffeine reduces the body weight of DIO mice by the suppression of appetite and increasing of energy expenditure. We also show that caffeine excites oxytocin expressing neurons, and blockade of the action of oxytocin significantly attenuates the effect of caffeine on energy balance. These data suggest that caffeine inhibits A1Rs expressed on PVN oxytocin neurons to negatively regulate energy balance in DIO mice.