Daily Endocrinology Research Analysis
Analyzed 76 papers and selected 3 impactful papers.
Summary
Analyzed 76 papers and selected 3 impactful articles.
Selected Articles
1. HRS-7535, an oral small-molecule GLP-1 receptor agonist, in Chinese adults with obesity without diabetes: a randomized, double-blind, placebo-controlled phase 2 trial.
In adults with obesity without diabetes, once-daily oral HRS-7535 achieved significant 26-week weight loss at doses ≥60 mg versus placebo (placebo-adjusted up to −6.87%). Gastrointestinal adverse events were mostly mild-to-moderate and occurred more during dose escalation, indicating an acceptable tolerability profile.
Impact: This is among the first randomized, double-blind trials to demonstrate clinically meaningful weight loss with an oral small-molecule GLP-1 receptor agonist, potentially widening access to incretin therapy beyond injectables.
Clinical Implications: If confirmed in longer and broader studies, oral GLP-1RA therapy could offer effective, convenient obesity treatment, supporting use at doses ≥60 mg with GI monitoring during titration.
Key Findings
- At week 26, LS mean weight change: −7.09% (60 mg), −6.17% (120 mg), −9.36% (180 mg) vs −2.50% (placebo).
- Placebo-adjusted LS mean differences: −4.60% (60 mg; P=0.0006), −3.67% (120 mg; P=0.0062), −6.87% (180 mg; P<0.0001).
- GI adverse events were the most common, predominantly mild-to-moderate, and more frequent during dose escalation.
Methodological Strengths
- Multicenter, randomized, double-blind, placebo-controlled phase 2 design with dose-ranging.
- Pre-specified primary endpoint (26-week percent weight change) with consistent efficacy across ≥60 mg doses.
Limitations
- 26-week duration limits assessment of long-term efficacy, safety, and cardiometabolic outcomes.
- Conducted in Chinese adults without diabetes; generalizability to broader populations and head-to-head comparisons versus injectable GLP-1RAs are lacking.
Future Directions: Confirmatory phase 3 trials should evaluate long-term efficacy/safety, cardiometabolic benefits, and head-to-head comparisons with injectable incretins, and assess applicability across diverse populations.
HRS-7535 is an orally active small-molecule glucagon-like peptide-1 receptor agonist that showed weight-loss potential in a phase 1 study. In this completed multicenter, randomized, double-blind, placebo-controlled phase 2 trial conducted at 29 centers in China, we evaluated the efficacy and safety of HRS-7535 in adults with obesity without diabetes. 235 participants with a body mass index of 28.0-40.0 kg/m² were randomized a 1:1:1:1:1 ratio to once-daily oral HRS-7535 at target doses of 30 mg (n = 48), 60 mg (n = 47), 120 mg (n = 46), or 180 mg (n = 48), or placebo (n = 46); all randomized participants were included in the analyses. Primary endpoint was percentage change in body weight from baseline to Week 26. At Week 26, least-squares (LS) mean percentage changes in body weight were -2.99% with 30 mg, -7.09% with 60 mg, -6.17% with 120 mg, and -9.36% with 180 mg, versus -2.50% with placebo. Corresponding placebo-adjusted LS mean differences were -0.49%, -4.60%, -3.67%, and -6.87% (P = 0.7104, 0.0006, 0.0062, and <0.0001, respectively). Gastrointestinal adverse events were the most common, were predominantly mild to moderate, and occurred more frequently during dose escalation. Overall, once-daily oral HRS-7535 at doses of 60 mg or higher produced clinically meaningful weight loss and was generally well tolerated.Trial registration: ClinicalTrials.gov identifier NCT06250946.
2. E4BP4 safeguards brown fat mitochondria from obesity-induced fragmentation via ceramide repression.
E4BP4 interacts with PRDM16 to repress Cers6 via a distal enhancer, lowering C16:0 ceramide in brown fat, thereby preventing obesity-induced mitochondrial fragmentation and preserving oxidative function. E4BP4 gain-of-function improved systemic glucose homeostasis independent of weight loss, positioning ceramide repression as a key axis for BAT health.
Impact: This study uncovers a transcriptional mechanism linking ceramide biosynthesis to mitochondrial dynamics in brown fat and demonstrates systemic metabolic benefits, opening avenues for ceramide-targeted therapies in obesity.
Clinical Implications: While preclinical, modulation of the E4BP4–PRDM16–Cers6 axis and ceramide levels could inspire strategies to preserve BAT function and improve glucose homeostasis in obesity.
Key Findings
- E4BP4 represses Cers6 by binding a 65 kb upstream enhancer and interacting with PRDM16, reducing C16:0 ceramide in BAT.
- E4BP4 prevents obesity-induced mitochondrial fragmentation and oxidative dysfunction in brown adipocytes.
- E4BP4 gain-of-function improves systemic glucose homeostasis independent of weight loss.
Methodological Strengths
- Multi-level mechanistic evidence including enhancer binding, protein–protein interaction, and lipidomic changes in vivo.
- Physiologic relevance demonstrated by improved systemic glucose homeostasis with E4BP4 gain-of-function.
Limitations
- Findings are preclinical and primarily in murine brown fat; translational applicability to humans remains to be established.
- The tissue specificity and potential off-target effects of modulating E4BP4 were not fully characterized.
Future Directions: Define the translatability of E4BP4–ceramide modulation in human BAT, assess safety of targeting this axis, and test pharmacologic ceramide-lowering strategies for metabolic disease.
Brown adipose tissue (BAT) counteracts obesity-related metabolic dysfunction through both thermogenic and non-thermogenic means. However, substantial evidence indicates that obesity negatively affects BAT mitochondrial morphology and oxidative capacity, impairing systemic energy homeostasis. Motivated by this apparent contradiction, we investigate the relationship between obesity and mitochondrial dynamics, as the underlying mechanisms remain incompletely understood. Here, we identify E4BP4 as a transcriptional repressor that prevents obesity-induced mitochondrial fragmentation and oxidative dysfunction by inhibiting ceramide synthesis in brown fat. Specifically, E4BP4 interacts with PRDM16 to repress Cers6 mRNA expression and consequently reduces C16:0 ceramide levels by binding to a 65 kb upstream enhancer region of the Cers6 gene. Notably, the preservation of mitochondrial integrity in BAT by E4BP4 gain-of-function improves systemic glucose homeostasis, independent of weight loss. Collectively, our findings establish E4BP4 as a molecular safeguard against obesity-induced mitochondrial fragmentation and oxidative dysfunction, primarily by suppressing ceramide synthesis in brown fat.
3. Aging and Western Diet Synergistically Impair Hepatic Thyroid Hormone Signaling to Promote Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in Mice.
In mice, aging and Western diet synergistically reduced intrahepatic T4/T3 and altered deiodinase activities (↓Dio1, ↑Dio3), worsening hepatic inflammation and fibrosis consistent with MASLD progression. The thyromimetic resmetirom attenuated hepatocyte senescence phenotypes, inflammasome activation and ER stress, and activated autophagy.
Impact: This study mechanistically connects aging-related thyroid hormone signaling defects to MASLD progression and identifies resmetirom as a senescence-modulating intervention, informing therapeutic strategies in aging-associated fatty liver disease.
Clinical Implications: Findings support evaluating thyromimetics like resmetirom in older MASLD patients and considering intrahepatic thyroid hormone status as a therapeutic target or biomarker.
Key Findings
- Aging plus Western diet synergistically reduced intrahepatic T4/T3 and worsened hepatic inflammation and fibrosis.
- Aging decreased Dio1 (activating deiodinase) and increased Dio3 (inactivating deiodinase), with diet- and age-dependent modulation.
- Resmetirom reduced senescence markers, SASP gene expression, inflammasome activation, ER stress, and activated autophagy in hepatocytes.
Methodological Strengths
- Integrated in vivo aging and dietary models with detailed measurements of intrahepatic TH levels and deiodinase activities.
- Complementary in vitro hepatocyte senescence model to probe mechanisms and pharmacologic rescue with resmetirom.
Limitations
- Mouse study with 8-week Western diet exposure; long-term and human translational validation are needed.
- Sex-specific effects and comprehensive systemic metabolic readouts were not fully delineated.
Future Directions: Translate findings to human MASLD by profiling intrahepatic TH signaling across age, testing resmetirom’s senescence-modulating effects clinically, and defining optimal patient subsets.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily driven by a Western-style diet and exacerbated with aging, yet underlying mechanisms remain unclear. Given the essential role of thyroid hormone (TH) in MASLD progression, we hypothesized that impaired intrahepatic TH action during aging promotes MASLD progression and severity of MASH with fibrosis. We evaluated hepatic TH metabolism in young (18-24 weeks) and old (108-120 weeks) C57BL/6J mice fed either a normal chow diet (NCD) or a Western diet with fructose (WDF) for 8 weeks. Liver histology, metabolic parameters, inflammatory and fibrotic markers, intrahepatic thyroxine (T4) and triiodothyronine (T3) concentrations, and activities of deiodinase enzymes (Dio1 and Dio3) were measured. Additionally, an in vitro hepatocyte senescence model using AML12 cells was employed to assess age-related alterations in deiodinase expression and the therapeutic efficacy of resmetirom (an FDA-approved thyromimetic). Aging and WDF synergistically exacerbated hepatic inflammation and fibrosis, accompanied by significant reductions in intrahepatic T4 and T3. Aging markedly decreased Dio1 activity, which converts T4 to active T3, whereas WDF partially restored Dio1 in old mice. Conversely, Dio3 activity, responsible for TH inactivation, increased with age but exhibited age-dependent differential responses to WDF, findings mirrored in senescent hepatocytes. Notably, resmetirom significantly reduced senescence markers, inhibited senescence-associated secretory phenotype (SASP) genes, inflammasome activation, endoplasmic reticulum (ER) stress, and activated autophagy. Collectively, our findings demonstrate that aging and stress by a Western-style diet synergistically impair hepatic TH signaling, accelerating MASLD progression. Furthermore, resmetirom improved hepatic senescence, highlighting its potential therapeutic repurposing for aging-associated hepatic pathologies, including MASLD.