bluuebunny/crossref_metadata_2025_split huggingface dataset:
1514-P: Is Low Birthweight Associated with Lower Adiponectin Levels? A Systematic Review and Meta-analysis
Authors: ALHAKEEM AFNAN S. , TÜRKOGLU ALEYNA , LAWAETZ TRINE W.H. , HELMS ANDERSEN TUE , BRØNS CHARLOTTE , VAAG ALLAN A. 
Published: June 2024

Background: Compared to people with normal birth weight (NBW), individuals born with low and high birth weights (LBW and HBW) are at increased risk of developing type 2 diabetes. Studies have suggested that this could be due to lower levels of the insulin-sensitizing adipokine adiponectin. We performed a systematic review and meta-analysis of studies that have reported circulating levels of adiponectin in relation to birthweight across all age groups to determine the extent to which levels of adiponectin are lower in LBW and/or HBW subjects, respectively.
Methods: Searching MEDLINE, Embase and Web of Science yielded a total of 1486 studies. Two independent reviewers screened studies against inclusion criteria and among these were 67 included in the meta-analysis. Using a random-effect model, two meta-analyses were carried out to calculate the pooled effect size and corresponding 95% confidence interval. Heterogeneity was assessed using the I2-test, and subgroup and meta-regression analyses performed to identify potential sources of variation.
Results: The first meta-analysis included 24 studies comparing adiponectin levels in LBW to NBW individuals. Pooled effect size revealed a statistically significant lower level of adiponectin in LBW compared to NBW individuals (SMD= -0.55 μg/ml [95% CI: -2.75; 1.65], P=0.02). The heterogeneity of results was significant (I2=92%, P&lt;0.01), but meta-regressions failed to identify sources of heterogeneity. The second meta-analysis included 15 studies comparing adiponectin levels between HBW and NBW subjects but failed to establish firm evidence of any significant difference in the overall effect size (SMD= -0.33 μg/ml [95% CI: -2.84; 2.17], P=0.28). Similar to the LBW analysis, significant heterogeneity was observed (I2=94%, P&lt;0.01).
Conclusion: Despite considerable heterogeneity between studies, there is firm evidence that LBW, but not HBW, subjects exhibit lower adiponectin levels compared to individuals born with NBW.

Disclosure
A.S. Alhakeem: None. A. Türkoglu: None. T.W.H. Lawaetz: None. T. Helms Andersen: None. C. Brøns: Stock/Shareholder; Novo Nordisk A/S. A.A. Vaag: None.
1531-P: Identification of a Novel Subset of Cold-Activated Hypothalamic Neurons That Stimulate Feeding
Authors: WATTS CHRISTINA A. , DEEM JENNIFER D. , REDFORD INGRID K. , BRYAN CAELEY , PHAN BAO ANH N. , DAMIAN VINCENT , SCARLETT JARRAD M. , SCHWARTZ MICHAEL W. , MORTON GREGORY J. 
Published: June 2024

Growing evidence suggests that the hypothalamus plays an important role in the coupling of thermoregulation to energy homeostasis. Based on preliminary evidence that neurons expressing tyrosine hydroxylase (TH) located in the rostral hypothalamus are activated by cold exposure, we sought in the current work to 1) map this previously unrecognized neural subpopulation and, 2) investigate its role(s) in the control of food intake. To this end, four groups of C57Bl6 mice were studied. Two of the groups either exposed to a cold (10 °C) or a warm environment (30 °C) for 90 min, while the other two were either fasted overnight or fed ad libitum (AL). Brains were then processed for immunohistochemical colocalization of cFos, a marker of neuronal activation, in TH(+) neurons. Our findings reveal that relative to mice housed in a warm environment, cold exposure increased the % of TH neurons expressing fos selectively in the periventricular hypothalamic nucleus (Pe) (22.5 ± 1.2% for cold vs. 5.0 ± 1.3% for warm, a ~4-fold increase; p&lt;0.001). In contrast, cFos was not detectably induced in TH(+) neurons located in the caudal PVN (p=ns). Overnight fasting had a similar effect to increase the % of PeTH neurons expressing cFos (26.0 ± 3.8% for fast vs. 13.4 ± 2.5% for fed, a ~2-fold increase; p&lt;0.05), but again was without effect in caudal PVNTH neurons. To determine whether activation of PeTH neurons is sufficient to increase food intake, TH-Cre animals received a unilateral microinjection of a Cre-inducible excitatory DREADD receptor directed to this brain area. Here, we found that relative to vehicle-treated controls, food intake was robustly increased following CNO-induced activation of PeTH neurons (0.94 ± 0.18g with CNO vs. 0.28 ± 0.09g with vehicle, a ~3-fold increase; p&lt;0.01). These findings implicate a novel set of cold-activated hypothalamic TH neurons in the regulation of food intake.

Disclosure
C.A. Watts: None. J.D. Deem: None. I.K. Redford: None. C. Bryan: None. B.N. Phan: None. V. Damian: None. J.M. Scarlett: None. M.W. Schwartz: None. G.J. Morton: Research Support; Novo Nordisk A/S.

Funding
NIDDK-T32 Diabetes, Obesity, and Metabolism Training Grant (T32DK007247)
1532-P: Expression of Fibroblast Growth Factor-1 by Medial Hypothalamic Neurons Is Required for Normal Glucose and Energy Homeostasis
Authors: CHOI PIQUE , BRYAN CAELEY , MORTON GREGORY J. , SCHWARTZ MICHAEL W. , SCARLETT JARRAD M. 
Published: June 2024

The brain is a primary target for the beneficial metabolic effects of members of the fibroblast growth factor (FGF) family. As one example, our group and others have shown that a single intracerebroventricular (icv) injection of fibroblast growth factor-1 (FGF1) induces both transient anorexia and weight loss and sustained remission of diabetic hyperglycemia in rodent models of type 2 diabetes (T2D). These pharmacological responses are mediated by FGF1’s action in the mediobasal hypothalamus (MBH), which includes both arcuate (ARC) and ventromedial hypothalamic nuclei (VMN). FGF1 is endogenously expressed in the MBH and based on both RT-PCR and western blot analysis of MBH punches from male C57Bl/6J mice, we report that Fgf1 mRNA levels were reduced by 33%, (p&lt;0.01) and FGF1 protein levels were reduced by 39%, (p&lt;0.01) during fasting while both were restored to baseline within 2 hours of refeeding. Given the key role played by the VMN neurons in both energy and glucose homeostasis, we sought to determine if endogenous VMN FGF1 signaling participates in these processes. We deleted FGF1 from MBH neurons by microinjecting either control AAV1-CAG-GFP or AAV1-hSyn-Cre-WPRE.hGH directed towards the bilateral MBH of adult male FGF1 floxed (FGF1fl/fl) mice. We found that although daily food intake tended to be higher following targeted deletion of FGF1, the effect did not achieve statistical significance. In contrast, this intervention caused significant weight gain (characterized by increases of both lean and fat mass), glucose intolerance, and pronounced disruption of dark/light cycle feeding, energy expenditure, and locomotion patterns. Together, these preliminary findings support the conclusion that expression of FGF1 by neurons in the MBH is required for normal energy and glucose homeostasis.

Disclosure
P. Choi: None. C. Bryan: None. G.J. Morton: Research Support; Novo Nordisk A/S. M.W. Schwartz: None. J.M. Scarlett: None.
1534-P: The Role of Differentially Located Mouse Intrapancreatic Neurons in Islet ß-Cell and Acinar Cell Function
Authors: TAMAYO ALEJANDRO M. , LEVI NOAH , MAKHMUTOVA MADINA , PEREIRA ELIZABETH , CAICEDO ALEJANDRO 
Published: June 2024

In the mouse, cholinergic neurons within the pancreas are organized in ganglia that can be classified based on their location: acinar ganglia embedded in the exocrine compartments versus neuroinsular ganglia located adjacent to endocrine islets. Although they form a network within the organ, it is unclear if this anatomical segregation allows channeling external input (e.g. efferent vagal input) to the pancreas in a labeled-line manner, thus differentially affecting exocrine and endocrine function. Our study aims to test the hypothesis that pancreatic innervation can be segregated into (1) acinar ganglia that preferentially target exocrine tissues controlling digestive enzyme secretion and (2) neuroinsular ganglia that preferentially target glucoregulatory endocrine islets. To test this hypothesis, we used the chemogenetic approach to stimulate cholinergic neurons in living pancreas slices from mice expressing DREADD receptors under the control of the choline acetyltransferase promoter (ChAT-hM3Dq DREADD mice). Our results showed that only cholinergic neurons express DREADD receptors and respond to CNO stimulation with a characteristic muscarinic response. We were able to measure Ca2+ responses in different tissue compartments. Acinar cells have a stronger Ca2+ response when compared with islet cells after neuronal stimulation. Ca2+ responses in the beta cell population were sparse, localized, and only at higher glucose concentrations. Acinar and islet beta cell activation were confirmed by increases in amylase and insulin secretion after neuronal stimulation from dynamic perfusion experiments. These preliminary results showed that the chemogenetic approach to target cholinergic neurons in living pancreas slices is a powerful platform for studying the effects of local neural activation on different cell populations providing the basis for future neuromodulation experiments.

Disclosure
A.M. Tamayo: None. N. Levi: None. M. Makhmutova: None. E. Pereira: None. A. Caicedo: None.
1535-P: Type 2 Diabetes Remission after Roux-en-Y Gastric Bypass Is Related to a Reduction of Pancreatic Noradrenergic Innervation and Beta-Cell Redifferentiation
Authors: CINTI FRANCESCA , AVOLIO ADRIANA , MORCIANO CASSANDRA , GUGLIANDOLO SHAWN , CAPECE UMBERTO , MEZZA TERESA , SOLDOVIERI LAURA , CICCARELLI GEA , DI GIUSEPPE GIANFRANCO , MOFFA SIMONA , GIACCARI ANDREA 
Published: June 2024

Background: β cell dedifferentiation has been identified as the process responsible for the functional "disappearance" of β cells from the islets of diabetic subjects.We recently demonstrated that the islets of diabetic subjects are about 3 times more innervated than controls, with a stepwise increase in innervation correlated with worsening glucose tolerance and a direct correlation with the dedifferentiation score. The remission of Type 2 Diabetes after bariatric surgery is well known but the mechanisms which determine it are still on debate.
Aim: to test the hypothesis that the anatomical removal of entero-pancreatic innervation induces a reduction of sympathetic innervation with the consequent re-differentiation of β cells, supporting the idea that innervation represents the key mechanism responsible for β cell dedifferentiation.
Methods: 10 obese diabetic rat Zucker FA/FA have been fasted overnight for 14 h followed by a glucose tolerance test (GTT) before and 6 weeks after the Roux-en-Y gastric bypass (RYGB) surgery (n=5) or sham (n=5). The morphological analysis of noradrenergic fibers and dedifferentiation score has been performed on the pancreas samples.
Results: total glucose level determined by area under the curve (AUC) resulted significantly reduced in the RYGB group compared to sham group (p&lt;0.0001) confirming the remission of type 2 diabetes after bariatric surgery. The number of noradrenergic fibers resulted significantly reduced in RYGB group compared to sham group (p=0.04) as well as the dedifferentiation score (p=0.01).
Conclusions: the data confirm that noradrenergic fiber might be directly involved in the process of dedifferentiation. The procedure of RYGB seems to induce a significant reduction of noradrenergic fibers with a consequent reduction of dedifferentiation score, providing a new potential explanation for the remission of type 2 diabetes after bariatric surgery.

Disclosure
F. Cinti: None. A. Avolio: None. C. Morciano: None. S. Gugliandolo: None. U. Capece: None. T. Mezza: None. L. Soldovieri: None. G. Ciccarelli: None. G. Di Giuseppe: None. S. Moffa: None. A. Giaccari: None.
1540-P: LRP1 in GABAergic Neurons Is a Key Link between Obesity and Memory Function
Authors: KIM YOUNG-BUM , RODRIGUES KELLEN , CHAN KIM SEUNG , CAMPOLIM CLARA , YOUNG JENNIE , YANG WON-MO 
Published: June 2024

Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, and its dysfunction has been linked to cognitive decline, dementia, and Alzheimer’s disease. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in obesity remains unexplored. Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) are subjected to conduct behavioral tests of locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. We evaluated the relationships between behavior outcomes and metabolic risk factors. Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function. In the spatial Y-maze test, Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice had a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in the contextual and cued fear conditioning tests, accompanied by increased neuronal necrosis and neuroinflammation in the hippocampus. Importantly, these memory deficits correlate negatively with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. Our findings demonstrate that LRP1 from GABAergic neurons is important in maintaining normal memory function. Metabolically, obesity caused by LRP1 deletion in GABAergic neurons negatively regulates memory and cognitive function. Thus, LRP1 in GABAergic neurons emerges as a key link between obesity and memory function, emphasizing its potential significance in maintaining neural system integrity associated with metabolism.

Disclosure
Y. Kim: None. K. Rodrigues: None. S. Kim: None. C. Campolim: None. J. Young: None. W. Yang: None.

Funding
National Institutes of Health (R01DK106076 and R01AG080842)
1543-P: Feeding Regulatory Mechanism of Leptin Action in the Nucleus of the Solitary Tract and Area Postrema
Authors: BRUCE KYLA , ZHANG SONG-YANG , KUAH RACHEL , LI ROSA J.W. , LAM TONY K. 
Published: June 2024

Obesity is associated with brain leptin resistance. Leptin action in the hypothalamus activates STAT3 to lower feeding and weight, but whether extrahypothalamic regions such as the nucleus of the solitary tract (NTS) and area postrema (AP) mediate leptin action and resistance remain elusive. Here, we conducted refeeding and signaling studies to determine the impact of leptin infusion into the NTS or AP of male rats on chow or 3-day HF diet. Leptin vs vehicle infusion into the NTS (0.5μg; 0.2μL for 5min) increased STAT3 phosphorylation [lep: 1.7±0.1 vs. veh: 1.0±0.1 pSTAT3/total STAT3 intensity; p&lt;0.01; n=6,6] and lowered food intake [lep: 77±5 vs. veh: 100±4 kCal; p&lt;0.01; n=11,10] within 24h of refeeding in chow rats, while leptin infusion into the AP failed to lower feeding [lep: 93±6 vs. veh: 92±5 kCal; n=10,6]. When leptin was co-infused with STAT3 cell-permeable peptide (9.8ng dose that blocks the enzyme's phosphorylation) into the NTS, leptin failed to exert effects on STAT3 [lep + inhibitor: 0.9±0.1 vs. lep: 1.7±0.1 pSTAT3/total STAT3 intensity; p&lt;0.01; n=5,6] and food intake [lep + inhibitor: 96±3 vs. lep: 77±5 kCal; p&lt;0.05; n=13,11]. In 3d HF-induced hyperphagic [HF: 275±2 vs chow: 225±7 kCal; p&lt;0.05; n=16,34] rats, NTS leptin vs vehicle failed to activate STAT3 [lep: 0.8±0.2 vs veh: 1±0.3 pSTAT3/total STAT3 intensity; n=5,5] or inhibit feeding [lep: 110±4 vs. veh: 113±3 kCal; n=10,6] in association with a reduction in leptin receptor expression in the NTS [HF: 0.68±0.02 vs. chow: 1±0.08; p&lt;0.01; n=7,10]. In summary, we discover that 1) leptin administration into the NTS, but not the AP, lowers feeding and the NTS effect is depended on STAT3 activation, 2) 3d of HF feeding induces leptin resistance in the NTS to activate STAT3 and lower feeding in parallel to a reduction in leptin receptor expression. Thus, we unveil NTS as a site for leptin-STAT3 signaling to lower feeding and HF-induced leptin resistance. In contrast, AP appears do not sense leptin to regulate feeding.

Disclosure
K. Bruce: None. S. Zhang: None. R. Kuah: None. R.J.W. Li: None. T.K. Lam: None.

Funding
CIHR PJT-189957
1544-P: Fructooligosacharides Supplementation Prevents Western Diet–Induced Hypothalamic Inflammation
Authors: MUNOZ MARCOS D. , YANG XIAOHUA , LUO PEI , TORRES IRIZARRY VALERIA C. , CARRILLO-SÁENZ LESLIE , PRIYADARSHINI MEDHA , LAYDEN BRIAN T. , XU PINGWEN 
Published: June 2024

Obesity is linked to 30-53% of new diabetes cases in the U.S. yearly. This project investigates how supplementation with fructo-oligosaccharides (FOS), a widely used dietary fiber, protects against diet induced obesity (DIO) by decreasing bodyweight (BW) and fat accumulation. The beneficial effects of FOS are largely attributed to the production of Short-Chain Fatty Acids (SCFA) through gut microbiota-mediated fermentation. Our findings indicate that supplementing a Western diet (WD) with 10% FOS for 8 weeks increases SCFA levels in the bloodstream, prevents weight gain in mice, and reduces markers of hypothalamic inflammation and microglial activation. Building on these findings, we further investigated the short-term effects of 7-day FOS supplementation. We found that adding 10% FOS to the WD completely prevented body weight gain and fat mass accumulation, while also lowering fasting blood glucose levels. Notably, mice treated with FOS maintained circadian oscillation of fuel utilization, as observed through the respiratory exchange ratio (RER), in contrast to WD-treated mice whose RER oscillation was disrupted within the first day of the diet. These protective effects were accompanied by reduced expression of hypothalamic interleukin-6 and iNOS after just 1 day of diet treatment. Taken together, our results suggest that early suppression of hypothalamic inflammation may be responsible for the beneficial effects of FOS supplementation. Understanding the mechanisms underlying the protective effects of FOS is a crucial step in developing new dietary strategies and therapeutic targets to address the obesity epidemic and its associated comorbidities.

Disclosure
M.D. Munoz: None. X. Yang: None. P. Luo: None. V.C. Torres Irizarry: None. L. Carrillo-Sáenz: None. M. Priyadarshini: None. B.T. Layden: None. P. Xu: None.

Funding
National Institutes of Health (R01DK123098)
1547-P: SGLT Inhibitor Canagliflozin Modulates Hypothalamic Function with Aging
Authors: SADAGURSKI MARIANNA , JAYARATHNE HASHAN M. 
Published: June 2024

The hypothalamus, a critical brain region intricately involved in metabolic regulation and homeostasis, undergoes substantial changes with aging, influencing age-related metabolic alterations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), such as Canagliflozin, are anti-diabetic agents that enhance glucose elimination, resulting in a net calorie loss. Previously, we demonstrated Canagliflozin's ability to extend the median lifespan of genetically heterogeneous UM-HET3 male mice and improve hypothalamic insulin responsiveness in aging males. Here, we sought to evaluate Canagliflozin's impact on hypothalamic metabolic function during aging. Energy homeostasis was measured in 12- and 26-month-old UM-HET3 mice treated with Canagliflozin from 7 months of age. Canagliflozin-fed mice exhibited increased food consumption and water intake. Notably, 12-month-old Canagliflozin-fed males, but not females, displayed a significant increase in energy expenditure compared to controls. By 26 months, both male and female Canagliflozin-treated mice exhibited elevated metabolic rates, indicating sustained effects. This shift in energy expenditure correlated with alterations in hypothalamic orexigenic and anorexigenic projections in aged mice. Subsequently, bulk RNA-seq analysis of the hypothalamus from Canagliflozin-treated mice at 12 and 26 months revealed sex-specific transcriptional signatures, impacting glycolysis, oxidative phosphorylation, and insulin receptor signaling in aged mice leading to alterations in metabolic pathways. Our findings suggest that Canagliflozin's metabolic and health span effects in genetically diverse mice may be linked to its central effects, presenting it as a promising geroprotective intervention with implications for age-related metabolic changes.

Disclosure
M. Sadagurski: None. H.M. Jayarathne: None.

Funding
National Institutes of Health (RF1AG078170NIH, R01ES033171)
1551-P: Impaired ß-Cell Responsiveness to Glucagon in Type 2 Diabetes Mellitus Assessed by a New C-Peptide Minimal Model
Authors: BOSCOLO FEDERICA , FAGGIONATO EDOARDO , VELLA ADRIAN , DALLA MAN CHIARA 
Published: June 2024

Glucagon (Gn) stimulates insulin secretion. However, tools to quantify β-cell responsivity to Gn are lacking. We therefore developed a novel method that provides quantitative indexes of β-cell function in response to a Gn bolus in people without (ND) and with type 2 diabetes (T2D).Eight ND individuals (3M, age = 55±9 yrs, BMI = 32±4 kg/m2) and 6 with T2D (1M, age = 59±5 yrs, BMI = 35±6 kg/m2) underwent a 210-min hyperglycemic clamp (~9 mmol/L). After 180 min, a 1 mg bolus of Gn was administered over 1 min and plasma Gn and C-peptide concentrations were frequently measured over 30 min. After testing a battery of mathematical models describing Gn-stimulated C-peptide secretion (CS), we selected one that assumes that CS is made up of two components, one proportional to the above basal Gn, through parameter Γs (static), and one proportional to Gn rate of change, through parameter Γd (dynamic responsivity to Gn). An index of total β-cell responsivity to Gn (Γtot) can also be calculated from Γs andΓd.Model estimated Γs, Γd, and Γtot were significantly lower in T2D compared to ND (p&lt;0.05), as shown in Fig. 1.
In conclusion, our findings reveal notable differences in both static, dynamic and total insulin secretory response between individuals with and without T2D, demonstrating that decreased β-cell responsiveness in T2D includes impaired responses to Gn as well as glucose.

Disclosure
F. Boscolo: None. E. Faggionato: None. A. Vella: Research Support; Novo Nordisk. Consultant; Hanmi Pharm. Co., Ltd., Crinetics Pharmaceuticals, Inc. Advisory Panel; Rezolute, Inc. C. Dalla Man: None.