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PubMed2026

AgRP reflects glucocorticoid action: integrated experimental and clinical evidence.

PURPOSE: Glucocorticoids (GCs) are key regulators of energy homeostasis. Clinically, patients with Cushing's syndrome exhibit obesity, whereas adrenal insufficiency is associated with weight loss. However, circulating biomarkers reflecting GC action have not been established. Agouti-related protein (AgRP), an orexigenic neuropeptide, is upregulated by GC in the rodent hypothalamus. Here, we investigated whether AgRP is a surrogate marker of GC action through in vitro and in vivo experiments as well as a clinical study. METHODS: The GC-dependent transcriptional regulation of AgRP was examined using reporter assays in neuronal BE(2)C cells. In animal experiments, the effects of GC on hypothalamic AgRP mRNA expression in C57BL/6J mice were examined. Circulating AgRP levels were also analyzed in nine patients with adrenal Cushing's syndrome before and after surgery. RESULTS: Two functional glucocorticoid-responsive elements (GREs) were identified in the human AgRP gene promoter, through which GC enhanced AgRP transcriptional activity. In mice, corticosterone (CORT) administration induced hyperphagia and increased hypothalamic AgRP mRNA levels, which positively correlated with plasma CORT levels. In patients with adrenal Cushing's syndrome, circulating AgRP levels significantly decreased after surgery (118.7 ± 40.3 vs. 37.7 ± 9.5 pg/mL, p < 0.01) and positively correlated with serum cortisol levels (r = 0.79, p < 0.01). CONCLUSION: These findings demonstrate that GC positively regulates AgRP across molecular, animal, and clinical settings, supporting the hypothesis that circulating AgRP may serve as a surrogate indicator of GC action. Further studies are warranted to establish its clinical applicability.

Animals↗

PubMed2025

FTO promotes weight gain via altering Kif1a splicing and axonal vesicle trafficking in AgRP neurons.

N6-methyladenosine (m6A) is an abundant chemical RNA modification involved in the regulation of many biological processes. The m6A demethylase FTO (fat mass and obesity-associated protein) is known to affect body weight, but its systemic context and underlying mechanisms remain unclear. Here, we found that mice lacking or overexpressing Fto in agouti-related peptide-expressing (AgRP) neurons in the hypothalamus exhibited decreased and increased body weight, respectively. FTO demethylated m6A on mRNAs for proteins associated with membrane trafficking and alternative splicing in AgRP neurons. Downstream, FTO-modulated alternative splicing of the axonal motor protein Kif1a affected its hinge region, which is relevant to the structure and function of KIF1A. Notably, Kif1a knockdown in AgRP neurons suppressed the weight gain of mice overexpressing Fto. In addition, FTO increased the trafficking and secretion of dense-core vesicles containing neuropeptides NPY and AgRP from AgRP neurons. Collectively, these results reveal a novel regulatory FTO-KIF1A axis in the brain affecting appetite-stimulating AgRP neurons and systemic energy homeostasis, via FTO regulation of the epitranscriptome of AgRP neurons.

Animals↗

PubMed2025

Shared and divergent acute cardiovascular risk protein responses to lipid infusion in women with and without PCOS.

AIMS: Elevated circulating lipids are linked to cardiovascular disease (CVD), especially in insulin-resistant states like polycystic ovary syndrome (PCOS), but their effects on cardiovascular risk proteins (CVRPs) remain unclear. This study used a two-step approach to examine acute cardiovascular proteomic responses to lipid-induced metabolic stress. We first identified proteins altered by lipids and insulin in healthy control (HC) women, then assessed whether these responses were similar or divergent in women with PCOS. METHODS: In a randomised cross-over study, 10 healthy controls and 12 women with PCOS underwent 5-h saline (control) or intralipid infusions. After 3 h, a 2-h hyperinsulinemic-euglycemic clamp was initiated. Plasma CVRP expression was assessed at baseline, post-lipid (180 min) and post-clamp (300 min) using SOMAscan proteomics. STRING and pathway enrichment analyses were performed to explore functional associations. RESULTS: In the HC group, lipid infusion altered the expression of 11 out of 54 CVRPs including increases in RANK, IL2RA, TACI, SLAF5 and DCN (p <0.05) and decreases in THPO, BOC, SOD2, FGF23, and AgRP (p <0.05). Most changes reversed with insulin, but BOC, SOD2, MMP12, FGF23, and DCN remained dysregulated. In PCOS, responses mirrored the HC group except for lower AgRP following lipid infusion (p <0.01), and persistent elevation of SLAF5 and DCN following insulin (p <0.05). Enrichment analysis linked altered proteins to immune activation, cell proliferation, and cytokine-receptor signalling. CONCLUSION: Acute lipid infusion revealed shared and phenotype-specific proteomic responses linked to early vascular stress. In PCOS, persistent dysregulation suggests reduced metabolic adaptability, with exploratory signals that may complement established biomarkers of early cardiovascular risk.

Humans↗