Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity.

Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT-NAD+-CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.

Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons.

Small humanin-like peptide 2 (SHLP2) is a mitochondrial-derived peptide implicated in several biological processes such as aging and oxidative stress. However, its functional role in the regulation of energy homeostasis remains unclear, and its corresponding receptor is not identified. Hereby, we demonstrate that both systemic and intracerebroventricular (ICV) administrations of SHLP2 protected the male mice from high-fat diet (HFD)-induced obesity and improved insulin sensitivity. In addition, the activation of pro-opiomelanocortin (POMC) neurons by SHLP2 in the arcuate nucleus of the hypothalamus (ARC) is involved in the suppression of food intake and the promotion of thermogenesis. Through high-throughput structural complementation screening, we discovered that SHLP2 binds to and activates chemokine receptor 7 (CXCR7). Taken together, our study not only reveals the therapeutic potential of SHLP2 in metabolic disorders but also provides important mechanistic insights into how it exerts its effects on energy homeostasis.

Obesity mechanism after hypothalamic damage: Cohort analysis of neuroimaging, psychological, cognitive, and clinical phenotyping data.

Objective: The hypothalamus regulates energy homeostasis, and its damage results in severe obesity. We aimed to investigate the multifaceted characteristics of hypothalamic obesity. Methods: We performed multidimensional analyses of brain structure/function and psychological and behavioral phenotypes in 29 patients with hypothalamic damage (HD) (craniopharyngioma) and 31 controls (non-functional pituitary adenoma). Patients underwent structural and functional magnetic resonance imaging and completed self-reports and cognitive tasks. Results: Patients with HD showed significantly higher postoperative weight gain than controls. The HD group also showed significant hypothalamic damage and lower neural activation in the left caudate nucleus in response to food images. The HD group had significantly higher food inattention, lower satiety, and higher restrained eating behavior. Within the HD group, higher restrained eating behavior was significantly associated with lower activation in the bilateral fusiform gyrus. Conclusion: These results suggest that hypothalamic damage contributes to weight gain by altering the brain response, attention, satiety, and eating behaviors. The present study proposes novel neuro-psycho-behavioral mechanisms targeted for patients with hypothalamic obesity.

Lateral hypothalamic leptin receptor neurons drive hunger-gated food-seeking and consummatory behaviours in male mice.

For survival, it is crucial for eating behaviours to be sequenced through two distinct seeking and consummatory phases. Heterogeneous lateral hypothalamus (LH) neurons are known to regulate motivated behaviours, yet which subpopulation drives food seeking and consummatory behaviours have not been fully addressed. Here, in male mice, fibre photometry recordings demonstrated that LH leptin receptor (LepR) neurons are correlated explicitly in both voluntary seeking and consummatory behaviours. Further, micro-endoscope recording of the LHLepR neurons demonstrated that one subpopulation is time-locked to seeking behaviours and the other subpopulation time-locked to consummatory behaviours. Seeking or consummatory phase specific paradigm revealed that activation of LHLepR neurons promotes seeking or consummatory behaviours and inhibition of LHLepR neurons reduces consummatory behaviours. The activity of LHLepR neurons was increased via Neuropeptide Y (NPY) which acted as a tonic permissive gate signal. Our results identify neural populations that mediate seeking and consummatory behaviours and may lead to therapeutic targets for maladaptive food seeking and consummatory behaviours.

Clinical Implication of Individually Tailored Segmentation Method for Distorted Hypothalamus in Craniopharyngioma.

Objective: Several attempts have been done to capture damaged hypothalamus (HT) using volumetric measurements to predict the development of hypothalamic obesity in patients with craniopharyngioma (CP). This study was to develop a novel method of HT volume measurement and examine the associations between postoperative HT volume and clinical parameters in patients with CP. Methods: We included 78 patients with adult-onset CP who underwent surgical resection. Postoperative HT volume was measured using T1- and T2-weighted magnetic resonance imaging (MRI) with a slice thickness of 3 mm, and corrected for temporal lobe volume. We collected data on pre- and postoperative body weights, which were measured at the time of HT volume measurements. Results: The corrected postoperative HT volume measured using T1- and T2-weighted images was significantly correlated (r=0.51 [95% confidence interval (CI) 0.32 to 0.67], P<0.01). However, HT volume was overestimated using T1-weighted images owing to obscured MR signal of the thalamus in patients with severe HT damage. Therefore, we used T2-weighted images to evaluate its clinical implications in 72 patients with available medical data. Postoperative HT volume was negatively associated with preoperative body weight and preoperative tumor volume (r=-0.25 [95% CI -0.45 to -0.04], P=0.04 and r=-0.26 [95% CI -0.40 to -0.15], P=0.03, respectively). In the subgroup analysis of CP patients who underwent primary surgery (n=56), pre- and postoperative body weights were negatively associated with HT volume (r=-0.30 [95% CI -0.53 to -0.03], P=0.03 and r=-0.29 [95% CI -0.53 to -0.02], P=0.03, respectively). Conclusions: Adult-onset CP patients showed negative associations between postoperative HT volume and preoperative/postoperative body weight using a new method of HT volume measurement based on T2-weighted images.

Central Regulation of Branched-Chain Amino Acids Is Mediated by AgRP Neurons.

Circulating branched-chain amino acids (BCAAs) are elevated in obesity and diabetes, and recent studies support a causal role for BCAAs in insulin resistance and defective glycemic control. The physiological mechanisms underlying BCAA regulation are poorly understood. Here we show that insulin signaling in the mediobasal hypothalamus (MBH) of rats is mandatory for lowering plasma BCAAs, most probably by inducing hepatic BCAA catabolism. Insulin receptor deletion only in agouti-related protein (AgRP)-expressing neurons (AgRP neurons) in the MBH impaired hepatic BCAA breakdown and suppression of plasma BCAAs during hyperinsulinemic clamps in mice. In support of this, chemogenetic stimulation of AgRP neurons in the absence of food significantly raised plasma BCAAs and impaired hepatic BCAA degradation. A prolonged fasting or ghrelin treatment recapitulated designer receptors exclusively activated by designer drugs-induced activation of AgRP neurons and increased plasma BCAAs. Acute stimulation of vagal motor neurons in the dorsal motor nucleus was sufficient to decrease plasma BCAAs. Notably, elevated plasma BCAAs were associated with impaired glucose homeostasis. These findings suggest a critical role of insulin signaling in AgRP neurons for BCAA regulation and raise the possibility that this control may be mediated primarily via vagal outflow. Furthermore, our results provide an opportunity to closely examine the potential mechanistic link between central nervous system-driven BCAA control and glucose homeostasis.

Bone health in neuromyelitis optica: Bone mineral density and fractures.

BACKGROUND: The bone health in neuromyelitis optica spectrum disorder with aquaporin-4 immunoglobulin G antibodies (NMOSD-AQP4) have not been fully evaluated. To evaluate the prevalence of fractures and bone loss in patients with NMOSD-AQP4 compared to healthy controls and patients with multiple sclerosis (MS) and to identify the risk factors associated with fractures and low bone mineral density (BMD) in patients with NMOSD-AQP4. METHODS: Seventy-one patients with NMOSD-AQP4 were included. The two control groups consisted of 213 age-, sex-, menopause-, and body mass index (BMI)-matched healthy participants from the Korean National Health and Nutrition Examination Survey (healthy controls) and 41 patients with multiple sclerosis (disease controls). We collected demographic and clinical data related to bone health including BMD and FRAX score. RESULTS: Patients with NMOSD-AQP4 had a higher prevalence of fractures than the healthy control group (OR = 5.40, CI = 2.004-14.524, p = 0.001), with falling, but not steroid use, being associated with an increased risk of fractures after diagnosis with NMOSD-AQP4 (OR = 24.902, CI = 3.086-200.947, p = 0.003). They also had significantly lower BMD than controls (femur neck, p = 0.044; total hip, p < 0.001), which was more prominent in young participants. The BMD in the NMOSD-AQP4 group was associated with cumulative dose of oral steroids, age, sex, BMI, and partly with the prophylactic calcium supplements. Though the patients with NMOSD-AQP4 did not differ significantly from patients with MS in terms of fracture rate and BMD, they had higher risk of fractures as measured by the Fracture Risk Assessment Tool (for major osteoporotic fractures, (p = 0.001; for hip fractures, p = 0.018). CONCLUSION: Patients with NMOSD-AQP4 had a significantly higher risk of fractures that could mostly be attributed to falling. Additionally, low BMD was observed in these patients; it was more prominent among young patients, associated with steroid use, and may partially prevented by the use of prophylactic calcium supplements.

High-phytate/low-calcium diet is a risk factor for crystal nephropathies, renal phosphate wasting, and bone loss.

Phosphate overload contributes to mineral bone disorders that are associated with crystal nephropathies. Phytate, the major form of phosphorus in plant seeds, is known as an indigestible and of negligible nutritional value in humans. However, the mechanism and adverse effects of high-phytate intake on Ca2+ and phosphate absorption and homeostasis are unknown. Here, we show that excessive intake of phytate along with a low-Ca2+ diet fed to rats contributed to the development of crystal nephropathies, renal phosphate wasting, and bone loss through tubular dysfunction secondary to dysregulation of intestinal calcium and phosphate absorption. Moreover, Ca2+ supplementation alleviated the detrimental effects of excess dietary phytate on bone and kidney through excretion of undigested Ca2+-phytate, which prevented a vicious cycle of intestinal phosphate overload and renal phosphate wasting while improving intestinal Ca2+ bioavailability. Thus, we demonstrate that phytate is digestible without a high-Ca2+ diet and is a risk factor for phosphate overloading and for the development of crystal nephropathies and bone disease.

Comparison of volumetric and shape changes of subcortical structures based on 3-dimensional image between obesity and normal-weighted subjects using 3.0 T MRI.

The morphological changes of the brain, particularly in the integrity of white and gray matter and the cortical thickness of brain, have been investigated extensively in obese patients. While there has been a growing amount of evidence indicating that subcortical structures are associated with obesity, studies on the volume of subregional level including shape alterations using high-field MRI are very sparse. The aim of this study was to evaluate and compare the volumes of 14 subcortical structures (bilateral thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens) in obese and normal-weighted subjects using 3T MRI for high resolution imaging. Fifty-four volunteers, 27 obesity (age = 23.15 ± 3.22, body mass index (BMI) = 30.12 ± 3.77) and 27 normal weighted controls (age = 26.1 ± 5.78, BMI = 21.76 ± 1.74) participated in the study. Through volumetric analysis, we found that the obese subjects had enlarged bilateral thalamus, putamen, pallidus and hippocampus, reduced bilateral caudate in obese groups in comparison to normal-weighted groups. Furthermore, we found that the medial-dorsal part of bilateral caudate significantly shrank while the lateral-dorsal part of bilateral thalamus significantly increased through vertex-based analysis (p < 0.05). Thus, based on our evidence, we suggest that subcortical structures are associated with feeding behavior and sensory function in obese patients.

Chemogenetic manipulation of parasympathetic neurons (DMV) regulates feeding behavior and energy metabolism.

Parasympathetic nervous system (PNS) innervates with several peripheral organs such as liver, pancreas and regulates energy metabolism. However, the direct role of PNS on food intake has been poorly understood. In the present study, we investigated the role of parasympathetic nervous system in regulation of feeding by chemogenetic methods. Adeno associated virus carrying DREADD (designer receptors exclusively activated by designer drugs) infused into the target brain region by stereotaxic surgery. The stimulatory hM3Dq or inhibitory hM4Di DREADD was over-expressed in selective population of dorsal motor nucleus of the vagus (DMV) neurons by Cre-recombinase-dependent manners. Activation of parasympathetic neuron by intraperitoneal injection of the M3-muscarinic receptor ligand clozapine-N-oxide (CNO) (1 mg/kg) suppressed food intake and resulted in body weight loss in ChAT-Cre mice. Parasympathetic neurons activation resulted in improved glucose tolerance while inhibition of the neurons resulted in impaired glucose tolerance. Stimulation of parasympathetic nervous system by injection of CNO (1 mg/kg) increased oxygen consumption and energy expenditure. Within the hypothalamus, in the arcuate nucleus (ARC) changed AGRP/POMC neurons. These results suggest that direct activation of parasympathetic nervous system decreases food intake and body weight with improved glucose tolerance.

Prevalence of vitamin D deficiency and effects of supplementation with cholecalciferol in patients with chronic kidney disease.

OBJECTIVE: We aimed to evaluate the vitamin D status, the effect of cholecalciferol supplementation, and the factors associated with vitamin D restoration in nondialytic patients with chronic kidney disease (CKD). DESIGN: The present study was a prospective open-label trial. SETTING: This study took place at the Seoul National University Boramae Medical Center. SUBJECTS: Patients with nondialytic CKD (estimated glomerular filtration rate [eGFR] 10-59 mL/min per 1.73 m(2)) participated in this study. INTERVENTION: Vitamin D status in 210 CKD patients was assessed and the patients with vitamin D deficiency (<30 ng/mL) were administered cholecalciferol (1,000 IU/day) for 6 months. MAIN OUTCOME MEASURE: The restoration rate of vitamin D deficiency at 3 and 6 months and the response-related factors were analyzed. RESULTS: The prevalence of vitamin D deficiency was 40.7% in CKD Stage 3, 61.5% in Stage 4, and 85.7% in Stage 5. The subgroup with vitamin D deficiency had a greater proportion of patients with diabetes, lower eGFR, and higher proteinuria. With the supplementation, 52 patients (76.5%) reached levels of 25-hydroxy vitamin D (25(OH)D) of 30 ng/mL or greater at 3 months, and the restoration of vitamin D was observed in 61 patients (89.7%) at 6 months. Lower levels of 25(OH)D and a higher amount of proteinuria at baseline were the factors associated with lower response to vitamin D supplementation. CONCLUSION: Vitamin D deficiency rate was high in nondialytic CKD patients, and the proportion increased as renal function decreased. A higher amount of proteinuria was the independent risk factor of nonresponse with supplementation. Vitamin D was replenished in most patients with cholecalciferol supplementation without any significant adverse effects.

National utilization of calcium supplements in patients with osteoporotic hip fracture in Korea.

BACKGROUND: Calcium is prescribed worldwide for patients diagnosed with osteoporosis. However, the national utilization of calcium and compliance with calcium is unclear in Korea. Our purpose is to evaluate Korea's national utilization of calcium and compliance with calcium in patients with osteoporotic hip fracture from 2007 to 2010 using data from the Health Insurance Review and Assessment (HIRA) Service. METHODS: From 2007 to 2011, osteoporotic hip fractures were identified using the International Classification of Diseases, 10th revision (ICD-10) and procedure code form from the nationwide database of the Health Insurance Review and Assessment Service. Compliant users of calcium were defined as the patients' medication possession ratio of 80 or more. We analyzed the compliance of calcium according to age and gender. RESULTS: Among 85,228 patients with hip fracture, 20,800 patients (24.4%) received a prescription of a calcium supplement. Among them, only 1,692 patients (8.1%) were identified as compliant users of calcium. The proportion of compliant users was higher in women than men in all age groups. The proportion of compliant users decreased with age in women. CONCLUSIONS: In Korea, the national utilization of calcium was low and compliance with calcium was unsatisfactory even in patients with osteoporotic hip fracture.