Abstract: This study explored how a high-fiber diet and n-3 fatty acids, alone and together, affect inflammation, oxidative stress, and blood sugar control in mice with type 2 diabetes. Forty diabetic mice were divided into four groups: diabetic control, high-fiber diet (25 g/day), n-3 PUFA (3 g/day), and a combined high-fiber + n-3 PUFA diet. The intervention lasted 16 weeks. The combined group showed the best outcomes, with CRP reduced by 48%, MDA lowered by 42%, SOD activity raised by 58%, and HbA1c decreased by 1.7 ± 0.2%. Gene analysis showed weaker NF-κB and MAPK signaling in the combined group than in single-treatment groups. These findings show that fiber and n-3 fatty acids work together through different but related actions: fiber supports gut health and reduces inflammation, while n-3 fatty acids improve antioxidant activity and help protect cells. This combination may offer a simple dietary approach to support blood sugar and metabolic balance in diabetes, though more long-term human studies are still needed.

Abstract: Pre-diabetes is a metabolic disorder characterised by higher than normal blood glucose levels, resulting in hyperglycemia. As a precursor to diabetes, pre-diabetes remains one of the most detrimental disorders for the larger global health. Improvement in understanding of the gut microbiome has led to the discovery of correlations between species present in the human gut microbiota and the onset of metabolic syndrome. Gut dysbiosis serves as a potent biomarker for the detection of pre-diabetes, and its progression into Type 2 Diabetes Mellitus (T2DM). Key biological processes, including metabolism, inflammation, insulin receptivity, and gut permeability, are impacted by the gut microbiota’s diversity of bacterial taxa and presence of short chain fatty acids (SCFAs), inflammatory markers, cytokines, metabolites, proteins, and lipopolysaccharides (LPS). These markers offer insight on the gut microbiome’s composition and support effective methods of intervention, including for the prevention of transition to T2DM. Obtaining and analyzing host microbiome data and integrating multi-omics approaches requires enhanced computational techniques, including advancements in machine learning. This offers personalised treatment for patients, including fecal transplants, diet, synbiotics, and anti-diabetic drugs. The gut microbiome’s potent influence on pre-diabetes serves as a future direction to improve patient care for glycemic disorders through enhanced therapeutic interventions.

Abstract: Bisphenol A (BPA), a common endocrine disruptor, poses a public health risk due to its potential effects on thyroid function. However, its role in thyroid cancer development remains unclear. This study investigated BPA's genotype-dependent effects on cellular processes in human thyroid cell lines. We exposed a non-tumorigenic thyroid cell line (Nthy-ori 3-1) and two papillary thyroid carcinoma cell lines, BCPAP (BRAF V600E) and TPC-1 (RET/PTC rearrangement), to BPA concentrations (0.1–1.0 µg/mL). Subse-quently, cellular viability, proliferation, and migration were assessed. BPA induced distinct genotype-dependent responses. At higher concentrations (0.8-1.0 µg/mL), non-tumorigenic cells exhibited significant dose-dependent cytotoxicity but paradoxi-cally showed enhanced migration. In the cancerous cell lines, TPC-1 cells did not ex-hibit inhibition of proliferation or changes in migration, while BCPAP cells were rela-tively resistant to cytotoxicity but showed reduced proliferation and significantly im-paired migration. Our findings demonstrate that BPA exerts dual and opposing effects on thyroid cells, depending on the genetic background. These genotype-specific sus-ceptibilities, cytotoxic and pro-migratory effects in normal cells, and in RET/PTC-positive cells, and antimigratory effects in BRAF-mutant cells underscore the complex role of BPA in thyroid pathophysiology. These results demonstrate that ge-netic background is a critical determinant of cellular susceptibility, suggesting that BPA exposure may differentially influence thyroid cancer initiation and progression.

Abstract: Zinc homeostasis is fundamental to metabolic health, orchestrated by the coordinated actions of two major zinc transporter families: ZIP (Zrt- and Irt-like Proteins) and ZnT (Zinc Transporters). ZIP-transporters Facilitates zinc influx into the cytosol from the extracellular space or from the lumen of intracellular organelles, whereas ZnT-transporters control zinc efflux from the cytosol to the extracellular space or facilitate its sequestration into intracellular vesicles and organelles, concurrently harboring the meticulous intracellular zinc homeostasis. This equilibrium is essential for all critical functions like cellular response, metabolic control, or immune pathway alteration. Disruption of this homeostasis is a driver of different pathological alterations like metabolic inflammation, a chronic low-grade inflammatory state underlying obesity, type 2 diabetes, and nonalcoholic fatty liver disease. Recent studies revealed that ZIP and ZnT transporters dynamically regulate metabolic and inflammatory cues, with their tissue-specific expression varying by tissue and acclimating to different physiological and pathological conditions. Recent advanced research in molecular and genetic understanding has helped to deepen our knowledge on the interplay of activity between ZIP and ZnT transporters and their crosstalk in metabolic tissues, underscoring the potential therapeutic prospect for restoring zinc balance and ameliorating metabolic inflammation. This review provides a comprehensive overview that covers the function, regulation, and the interactive crosstalk of ZIP and ZnT zinc transporters in metabolic tissues, and its pathological condition.

Abstract: Obesity treatments increasingly target multiple pathways beyond appetite suppression. We evaluated KBN2202, a salicylate-derived small molecule, in a high-fat diet (60% kcal) mouse model using female and male C57BL/6J mice treated for 8 weeks with oral KBN2202 (20 mg/kg/day) or matched-volume vehicle (1% DMSO/PBS). Body weight and food intake were tracked weekly; serum hormones/cytokines, adipose tissue histology, and open-field behavior were assessed at study end. KBN2202 significantly reduced peri-ovarian gonadal white adipose tissue (gWAT) mass and adipocyte size in females without altering overall body weight. Circulating glucagon-like peptide-1 (GLP-1) increased, uncoupling protein 1 (UCP1) in gWAT showed a non-significant upward trend, and serum TNF-α was selectively decreased, while MCP-1 and IL-1β were unchanged. Despite higher apparent food intake, locomotor activity was unaltered and anxiety-like behavior was reduced. Male mice did not show comparable adipose effects. These findings indicate depot-specific, peripheral modulation of adipose remodeling, hormonal balance, and inflammatory tone by KBN2202, supporting its further investigation as an adipose-targeted metabolic modulator complementary to incretin-based therapies.

Abstract: The objective is to identify the risk factors associated with the development of necrotizing enter-ocolitis in newborns less than 34 weeks old in the INMP ICU during the period 2020-2022. The approach is basic, quantitative, non-experimental, and longitudinal, taking into account a total population of 20,371 newborns treated, but 7.95% of cases (1,620 patients) received an exclusive diagnosis of necrotizing enterocolitis (NEC). Information processing was carried out using the multiple linear regression model with NEC as the dependent variable. The results showed that in the INMP ICU, 7.95% of newborns treated were diagnosed exclusively with necrotizing entero-colitis (NEC). A multiple linear regression model was implemented using the stepwise technique, with NEC as the dependent variable and various independent variables, including maternal, ne-onatal, and other factors related to medical care. Several risk factors associated with the devel-opment of necrotizing enterocolitis in premature newborns under 34 weeks of age in the INMP ICU were identified. These include, among others, chorioamnionitis, neonatal sepsis, and age of occurrence. The presence of chorioamnionitis was shown to be a significant risk factor, with a 0.754-unit increase in the odds of NEC for each unit increase. Neonatal sepsis was also significantly associated with a 1.114-unit increase in the odds of NEC for each unit increase. Therefore, these findings underscore the importance of identifying and adequately managing the risk factors as-sociated with necrotizing enterocolitis in neonatal care in the INMP ICU.

Abstract: The detailed characterization of antigen-specific serum antibodies is hindered by the lack of efficient, gentle isolation methods. Standard column affinity chromatography, despite being a powerful purification tool, presents practical challenges for this application, including high antigen consumption, and elution conditions that risk inducing antibody polyreactivity. Conventional acidic elution often compromises antibody integrity. This study introduces a novel microscale method for isolating specific immunoglobulins using anionic detergents as mild eluents. We employed antigen-functionalized hydrogel microarrays and magnetic beads as micro-immunosorbents. Among the detergents tested, sodium lauroyl glutamate (SLG) was optimal, achieving up to 78.3% recovery of functional antibodies. The optimized protocol including recovering G25-Sephadex gel filtration step effectively isolated specific antibodies from complex serum, with functional bioactivity retained between 58.5% and 85.3%. Multiplex immunoassays confirmed the high specificity of the isolated antibodies and the absence of detergent-induced polyreactivity. The method was successfully adapted for both specific antibody (virus, dietary and autoimmune) and total IgG isolation, demonstrating versatility across platforms. This work establishes a robust, efficient, and gentle workflow for obtaining high-purity, bioactive antibodies, enabling their subsequent in-depth analysis for research applications.

Abstract:

Background: Local specific biomarkers for MASLD risk stratification are urgently needed in Argentina. Aim: To characterized the interaction of gut microbiome signatures, genetic and clinical risk factors for MASLD in diabetics from different regions of Argentina. Material Methods: We recruited 214 diabetics from different regions. Anthropometric, clinical, and lifestyle data were obtained from all participants, who also underwent abdominal ultrasound for MASLD diagnosis and oral swabbing. PNPLA3 gene was amplified by PCR from the swabs, and rs738409 genotype was determined by bidirectional sequencing. To profile the MASLD-associated microbiome, stool was collected from 170 participants. V4 16S rRNA gene sequencing was performed and reads were analysed using QIIME2 2024.10.1. R Studio 2022.12.0 was used for statistical analyses. Results: MASLD prevalence was 77.9%, with similar rates in all regions. FIB-4 scores <1.3 and >2.67 were detected in 55.3% and 7.4% of patients, respectively. Half of diabetics had PNPLA3-GG genotype, with the highest rates in Northwestern Argentina (64.9%; p=0.02 vs Buenos Aires). PNPLA3-GG genotype was an independent risk factor for FIB-4 score (p=0.0008), and a protective factor against HbA1c (p=0.004), fasting plasma glucose (p=0.008), and cholesterol levels (p=0.02). Marked regional differences were observed in microbiota diversity and composition in Argentina. After adjusting for geographical region, Negativibacillus genus was exclusively detected in diabetics with MASLD and GG carriers. Catenibacterium genus was related to FIB-4>2.67. Short-chain fatty acids-producing bacteria were linked to absence of MASLD. Conclusions: These specific signatures could be potentially useful as MASLD biomarkers for risk stratification in diabetics from Argentina.

Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder in both children and adults. Pediatric MASLD, however, is not simply an early form of adult disease, as it exhibits distinct developmental, histological, and metabolic features. These characteristics reflect the complex, multi-hit, developmental continuum that begins in utero. Maternal obesity, gestational diabetes, and poor diet quality during pregnancy are linked to hepatic steatosis in offspring, implicating intra-uterine exposure to dyslipidemia, hyperglycemia, and excess free fatty acid flux as ini-tiators of fetal hepatic lipid deposition. After birth, feeding behaviors such as a prolonged duration of breastfeeding appears protective, while formula feeding, especially high added-sugar formulations, may accelerate rapid weight gain and predispose to later steatosis. Early childhood diets high in added sugars, saturated fats, and ultra-processed foods may further promote hepatic lipogenesis and inflammation and reveal underlying genetic susceptibility to metabolic dysfunction. This narrative review summarizes recent human and translational studies examining the relationship between prenatal, postnatal, and early childhood nutrition and offspring hepatic lipid accumulation, emphasizing early-life windows for intervention to reduce the burden of pediatric MASLD.

Abstract: This review focuses on the molecular pathogenesis of Type 1 diabetes (T1D), specifically on the key autoantigens targeted by the autoimmune response and the clinical implications of their epitope specificity. T1D is characterized by the destruction of insulin-producing pancreatic β-cells. The autoimmune attack is directed against a defined set of autoantigens, primarily insulin, glutamic acid decarboxylase 65, tyrosine phosphatase-like protein, zinc transporter 8, as well as several minor autoantigens. A critical advancement in understanding the disease has been the analysis of epitope specificity, revealing that immunodominant epitopes are conformational and often localized to C-terminal protein regions, exposed during β-cell degradation. The introduction of sensitive multiplex assays for the simultaneous detection of T1D-associated autoantibodies represents a major diagnostic breakthrough. These platforms enable early diagnosis, risk stratification, and the identification of a "therapeutic window" for intervention. At this preclinical stage, antigen-specific immunotherapies aimed at restoring immune tolerance show significant promise. Ultimately, the combination of personalized diagnostic profiles, epitope mapping, and targeted therapies forms the basis for a new T1D management paradigm focused on halting the autoimmune process itself and preserving functional β-cell mass.

Abstract: Insulin resistance (IR) describes impaired hormone signaling that triggers compensatory homeostatic responses resulting in hyperinsulinemia, increased accumulation of fatty substrates, lipotoxicity, oxidative stress, inflammation, cell death and fibrosis in target tissues. These processes ultimately lead to organ dysfunction and predispose certain individuals to various types of cancer. In this context, we will review the molecular pathogenesis and clinical significance of IR, its role in ‘metaflammation’, and the damage caused by IR in the pancreas, cardiovascular system, liver, and kidneys. Additionally, we will discuss principles of drug treatment for IR and outline a research agenda in this field.

Abstract: Previous studies suggest that the cortisol awakening response (CAR) shows a biphasic pattern—either an increase or a blunting—in reaction to exercise involving overload. These changes are considered to reflect physiological adaptation to exercise. However, the effects of continuous exercise on CAR under controlled experimental conditions have not been sufficiently explored. This study examined changes in CAR in response to short-term, continuous high-intensity cycling exercise over a 10-day period. Two healthy male participants underwent 12 consecutive days of experimental sessions: 2 baseline rest sessions followed by 10 days of cycling exercise sessions (20 min/day at 80% of maximal oxygen uptake [VO₂max]). CAR was measured daily throughout this period. Acute physiological responses and aerobic capacity were also assessed. Results showed that CAR increased during Days 1–4 of the exercise period and returned to baseline levels from Day 5 onward. Similar trends were observed in physiological responses. Additionally, participants demonstrated improvements in VO2max and/or maximum workload following the experimental sessions. These findings suggest that CAR could be a useful non-invasive biomarker for monitoring short-term physiological adaptation to high-intensity exercise.

Abstract: Women often notice monthly shifts in energy, mood, and appetite, prompting questions about whether lunar phases also play a role. This paper synthesizes current literature to explore how menstrual cycle–driven hormonal fluctuations—particularly shifts in estrogen and progesterone—affect macronutrient metabolism, cravings, and exercise performance, with a focus on increased appetite and subtle performance variations in the luteal phase. It further examines evidence for potential lunar effects, including studies suggesting modest correlations between moon phases, menstrual onset timing, and sleep disruptions, even though modern lifestyles often obscure such rhythms. For those who do not menstruate—such as postmenopausal women—adopting a monthly or “lunar” framework may still help address cyclical changes in mood or energy. Practical recommendations highlight “cycle syncing” via chrononutrition (aligned meal timing and composition) and targeted exercise based on hormonal states, while also acknowledging debates around any direct lunar impact. Ultimately, emerging findings emphasize the importance of personalized tracking, and future research with rigorous hormonal verification and sleep monitoring is needed to clarify the extent to which lunar considerations enhance health outcomes.

Abstract: Background/Objectives: Type 2 diabetes and obesity present escalating global health and economic challenges, highlighting the need for therapies that can effectively manage glycemic levels and reduce excess adiposity. Semaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist available in subcutaneous or oral formulation, has quickly evolved from a theoretical concept to a crucial component of modern metabolic care. This review explores the comprehensive development journey of semaglutide, drawing on evidence from medicinal chemistry, animal studies, initial human trials, the pivotal SUSTAIN and STEP programs, and real-world post-marketing surveillance. Methods: We conducted a detailed analysis of preclinical data sets, Phase I–III clinical trials, regulatory documents, and pharmaco-epidemiological studies published between 2008 and 2025. Results: Through strategic molecular modifications, such as specific amino-acid substitutions and the addition of a C18 fatty-diacid side chain to enhance albumin binding, the half-life of the peptide was extended to approximately 160 hours, allowing for weekly dosing. Studies in rodents and non-human primates showed that semaglutide effectively lowered blood glucose levels, reduced body weight, and preserved β-cells while maintaining a favorable safety profile. Phase I trials confirmed consistent pharmacokinetics and tolerability, while Phase II trials identified 0.5 mg and 1.0 mg once weekly as the most effective doses. The extensive SUSTAIN program validated significant reductions in HbA1c levels and weight loss compared to other treatments, as well as a 26% decrease in the relative risk of major adverse cardiovascular events (SUSTAIN-6). Subsequent STEP trials expanded the use of semaglutide to chronic weight management, revealing that nearly two-thirds of patients experienced a body weight reduction of at least 15%. Regulatory approvals from the FDA, EMA, and other regulatory agencies were obtained between 2017 and 2021, with ongoing research focusing on metabolic dysfunction-associated steatohepatitis, cardiovascular events, and chronic kidney disease. Conclusions: The trajectory of semaglutide exemplifies how intentional peptide design, iterative translational research, and outcome-driven clinical trial design can lead to groundbreaking therapies for complex metabolic disorders.

Abstract: Progesterone (P4) withdrawal is the key trigger for labor onset. Labor is a sterile inflammatory process involving monocyte infiltration, differentiation into M1 or M2 macrophages (Macs) and contributing to the inflammatory milieu in the uterus. Premature leukocyte influx may lead to preterm birth. Inflammatory stimuli induce intracellular progesterone (P4) withdrawal in myometrial cells (MYO) through activation of P4 metabolizing enzyme 20alpha-hydroxysteroid dehydrogenase (20α-HSD). We hypothesized that; (1) the pro-inflammatory M1-Macs induce 20α-HSD in MYO, which causes P4 withdrawal and MYO contractility; and (2) IL-1α produced by M1-Macs mediate the effect of M1-Macs on intracellular P4 withdrawal in MYO. Human myometrial biopsies from women in labor (TL) and not in labor (TNL) revealed higher IL-1α in TL, with M1-Macs in TNL expressing more IL-1α than MYO. In-vitro study shows; (1) higher expression of IL-1α in M1-Macs compared to M2-Macs; (2) treatment of MYO with IL-1α or M1-Macs increased 20α-HSD and contractility; and (3) blockade of IL-1α, AP-1 transcription factors, or co-treatment with non-metabolizable progestin; R5020 inhibits these effects. Our findings highlight the role of tissue-resident M1-Macs in regulating intracellular P4 metabolism and suggest that M1-Macs-derived IL-1α may facilitate P4-withdrawal and uterine contractility associated with labor onset.

Abstract: Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, yet the transcriptional hierarchies linking endocrine signaling to tumor progression remain poorly defined. Here, we integrated gene-expression profiles from two independent cohorts (TCGA-THCA and GSE33630) to identify consensus transcriptional master regulators (TMRs) driving PTC. After normalization and differential expression analysis, we reconstructed regulon networks with ARACNe-AP, inferred TMR activity using VIPER, and integrated evidence across datasets via Fisher’s meta-analysis. This cross-cohort strategy yielded 50 shared TMRs, predominantly from the Zinc Finger, Forkhead, ETS, and nuclear receptor families. Network topology highlighted PBX4, GATAD2A, BHLHE40, HEY2, and TEAD4 as upstream regulators controlling other TMRs. Functional enrichment revealed activation of NOTCH, MAPK, PI3K, and TGF-β signaling and enrichment of early and late estrogen-response programs, uncovering a noncanonical role of SMAD9 in TGF-β signaling. Together, these findings delineate the transcriptional and hormonal circuitry underlying thyroid tumorigenesis, providing a regulatory framework for biomarker-driven therapies based on network activity states.

Abstract: Background: Beta-lactoglobulin (BLG) is a protein found within whey protein (WP) that is rich in essential amino acids, most notably, leucine (LEU). LEU is considered the most potent EAA in the postprandial stimulation of muscle protein synthesis (MPS), such that sub-optimal protein/essential amino acid (EAA) doses containing higher LEU content elicit muscle anabolism comparable to larger protein doses. Here we explored the effects of naturally LEU-rich BLG (~10 g protein) versus isonitrogenous whey protein isolate (WPI, ~10g) on MPS. Methods: Ten healthy young men (26 ± 2 y; 179 ± 2 cm; 81 ± 3 kg) received BLG (1.57g LEU) or WPI (1.02g LEU) in a randomised double-blind cross-over fashion. A primed constant intravenous infusion of [1,2 13C2] LEU was used to determine MPS (isotope ratio mass spectrometry) at baseline and in response to feeding (FED) and feeding-plus-exercise (FED-EX; 6X8 unilateral leg extensions; 75% 1-RM). Plasma insulin and EAA’s were quantified. Results: Plasma EAA, branched chain amino acid (BCAA) and LEU concentrations increased rapidly following both protein supplements but exhibited a significantly greater EAA/BCAA/leucinemia, following BLG (P< 0.05 for all). MPS increased significantly in both FED and FED-EX (n = 8) states, with no significant differences evident between supplements. Conclusions: Both BLG and WPI effectively stimulated MPS doses in young healthy males, with BLG offering an advantage in EAA/BCAA/leucine bioavailability. It follows that future research should explore the potential of BLG in populations exhibiting anabolic resistance and exercise anabolism-deficiency, such as older adults, also in frail and clinical populations, to assess its utility in preserving muscle mass under conditions of sub-optimal protein intake.

Abstract: Cataract, the leading cause of blindness worldwide, results from progressive lens opacification driven by oxidative stress, protein aggregation, and metabolic dysregulation. While aging remains the primary risk factor, systemic metabolic disorders, particularly metabolic syndrome (MetS), are increasingly recognized as major contributors to cataractogenesis. MetS, a constellation of central obesity, hypertension, hyperglycemia, and dyslipidemia, exacerbates oxidative stress, inflammation, and metabolic imbalance, thereby accelerating lens degeneration.A novel and largely unexplored mechanism underlying MetS-induced cataract involves dysfunction of caveolae, cholesterol-rich plasma membrane microdomains composed of caveolin proteins. Caveolae are highly expressed in lens epithelial cells and play essential roles in nutrient transport, insulin signaling, lipid trafficking, and oxidative stress regulation. Disruption of caveolae integrity in MetS impairs insulin receptor, PI3K/Akt signaling, reduces glucose uptake, and compromises lens cell survival. In parallel, loss of caveolae function diminishes antioxidant buffering capacity and alters lipid homeostasis, promoting lipid peroxidation, membrane instability, and crystallin aggregation. These processes collectively establish a pro-cataractogenic microenvironment, linking systemic metabolic dysfunction to lens pathology through a unique membrane-based pathway.Clinically, cataracts in patients with MetS often present with similar visual symptoms to age-related forms but demonstrate earlier onset and faster progression, especially under poorly controlled metabolic conditions. Recognition of caveolae-dependent pathways as mediators of this process not only provides a new perspective on cataract pathophysiology but also opens the possibility of integrated co-treatment strategies. Therapeutic strategies that restore caveolae function through molecular interventions, antioxidant therapy, and systemic metabolic control may offer a unified approach to slowing both MetS progression and cataract development. Elucidating this unexplored mechanism holds promise for the design of innovative, dual-targeted therapies for patients with coexisting metabolic and ocular disease.

Abstract: Background/Objectives: Osteopenia predisposes to osteoporosis and fracture, especially at the femoral neck and spine. Conventional calcium supplements offer modest benefit with tolerability limits. CalGo®, a salmon bone complex (calcium hydroxyapatite, colla-gen, trace minerals), may support skeletal health. We evaluated its efficacy and safety in postmenopausal women with osteopenia. Methods: In a 24-month, randomized, dou-ble-blind, placebo-controlled trial, 80 women aged 50–80 years with DXA-confirmed fem-oral-neck osteopenia were assigned to daily CalGo® (n=40) or placebo (n=40). The prima-ry endpoint was 24-month change in femoral-neck BMD (g/cm²) analyzed by base-line-adjusted linear regression; secondary outcomes were lumbar spine and distal radius BMD, serum bone turnover markers (β-CTX-I, P1NP), health-related quality of life, and safety. Results: The primary analysis included participants with 24-month DXA (CalGo® n=29; placebo n=30). Femoral-neck BMD was maintained with CalGo® (+0.003 g/cm²; +0.4%) but declined with placebo (–0.017 g/cm²; –2.4%), yielding a significant base-line-adjusted between-group difference of +0.019 g/cm² (95% CI 0.001–0.038; p=0.044). Lumbar-spine loss was attenuated with CalGo® (–0.005 g/cm²; –0.3%) versus placebo (–0.028 g/cm²; –3.4%); the adjusted difference favored CalGo® (+0.026 g/cm²; p=0.058), and ≥1% spine gain was more likely with CalGo® (32.5% vs 11.4%; OR 3.61; p=0.043). No treatment effects were seen at the distal radius, in bone turnover markers, or in EQ-5D/EQ-VAS. CalGo® was well tolerated, with low adverse-event rates and no hepatic or renal safety signals. Conclusions: Over 24 months, CalGo® preserved femoral-neck BMD and attenuated lumbar-spine loss in osteopenic postmenopausal women, with a favorable safety profile.

Abstract: Dysregulated lipid metabolism is associated with cardiovascular disease, obesity and type 2 diabetes. In the current report we explore the functional interactions between two im-portant regulators of lipid metabolism, sterol regulatory element-binding protein 1 and 2 (SREBP1/2) and PRDI-BF1 and RIZ homology domain containing 16 (PRDM16). The SREBP family of transcription factors regulate cholesterol and fatty acid synthesis and metabolism, primarily in liver but also in white adipose tissue. PRDM16 is a major regulator of brown adipose tissue (BAT) biogenesis and function, and an inhibitor of white adipogenesis. We find that PRDM16 interacts with the nuclear forms of SREBP1/2 and inhibits their transcriptional activities. Consequently, inactivation of PRDM16 enhances the expression of well-established SREBP target genes involved in fatty acid and cho-lesterol synthesis/metabolism. Importantly, PRDM16 inactivation increases the expression of LDL receptor mRNA and protein and augments the cellular uptake of LDL particles. Supporting these findings, PRDM16-deficient cells accumulate more neutral lipids in a SREBP1/2-dependent manner. Inactivation of PRDM16 in white and brown preadipocyte cell lines and human adipose-derived stem cells enhances the expression of SREBP target genes. In addition, the expression of adipogenic markers was increased in mature white adipocytes generated from PRDM16-knockdown preadipocytes. Thus, our study identifies PRDM16 as a novel inhibitor of SREBP-dependent lipid metabolism with implications for adipose biology and metabolic disease.