Genetic Deletion of RHAMM Alleviates Hepatic Oxidative Stress, Reversing Thyroid Stimulating Hormone Elevation in Male Obese Mice

TY - JOUR

T1 - Genetic Deletion of RHAMM Alleviates Hepatic Oxidative Stress, Reversing Thyroid Stimulating Hormone Elevation in Male Obese Mice

AU - Wang, Tianzhen

AU - Sun, Helin

AU - Banah, Ayman

AU - Weng, Xiong

AU - Dayalan Naidu, Sharadha

AU - Kisielewski, Dot

AU - Ang, Abel

AU - Hayes, John

AU - Dinkova-Kostova, Albena

AU - Kang, Li

N1 - © 2025 by the authors

PY - 2025/9/16

Y1 - 2025/9/16

N2 - Objective: Obesity induces hypothyroidism with unknown mechanisms. This study investigates the role of (Receptor for Hyaluronan-Mediated Motility (RHAMM) in obesity-associated thyroid dysfunction, focusing on hepatic oxidative stress. Methods: Global RHAMM-deficient mice and their wildtype littermate controls were fed a normal chow diet or high-fat diet (HFD) for 16 weeks. Thyroid function was evaluated by measuring plasma thyroid-stimulating hormone (TSH) levels. The hepatic oxidative response was assessed by measuring signaling pathways associated with nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Results: HFD feeding increased plasma TSH levels in male mice but not in female mice. RHAMM deletion in male mice mitigated HFD-induced TSH elevation, which was associated with enhanced hepatic antioxidant defenses and reduced inflammation. This was evidenced by elevated expression of the Nrf2 target gene NAD(P)H: quinone oxidoreductase 1 (Nqo1), reduced protein carbonylation and nitration levels, and reduced expression of the pro-inflammatory cytokines IL-1β and TNF-α in livers of male RHAMM-deficient mice. Mechanistically, RHAMM deletion decreased AKT/ERK signaling, increased GSK3 signaling, increased CD44 protein expression, and increased Nqo1 levels in the liver. Conclusions: RHAMM promotes obesity-induced thyroid dysfunction by regulating oxidative stress and inflammation in male mice. Targeting RHAMM may provide a novel therapeutic strategy for mitigating obesity-related endocrine and metabolic disorders.

AB - Objective: Obesity induces hypothyroidism with unknown mechanisms. This study investigates the role of (Receptor for Hyaluronan-Mediated Motility (RHAMM) in obesity-associated thyroid dysfunction, focusing on hepatic oxidative stress. Methods: Global RHAMM-deficient mice and their wildtype littermate controls were fed a normal chow diet or high-fat diet (HFD) for 16 weeks. Thyroid function was evaluated by measuring plasma thyroid-stimulating hormone (TSH) levels. The hepatic oxidative response was assessed by measuring signaling pathways associated with nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Results: HFD feeding increased plasma TSH levels in male mice but not in female mice. RHAMM deletion in male mice mitigated HFD-induced TSH elevation, which was associated with enhanced hepatic antioxidant defenses and reduced inflammation. This was evidenced by elevated expression of the Nrf2 target gene NAD(P)H: quinone oxidoreductase 1 (Nqo1), reduced protein carbonylation and nitration levels, and reduced expression of the pro-inflammatory cytokines IL-1β and TNF-α in livers of male RHAMM-deficient mice. Mechanistically, RHAMM deletion decreased AKT/ERK signaling, increased GSK3 signaling, increased CD44 protein expression, and increased Nqo1 levels in the liver. Conclusions: RHAMM promotes obesity-induced thyroid dysfunction by regulating oxidative stress and inflammation in male mice. Targeting RHAMM may provide a novel therapeutic strategy for mitigating obesity-related endocrine and metabolic disorders.

KW - RHAMM

KW - obesity

KW - thyroid dysfunction

KW - oxidative stress

KW - Nrf2

UR - https://www.scopus.com/pages/publications/105017184784

U2 - 10.3390/cells14181448

DO - 10.3390/cells14181448

M3 - Article

C2 - 41002415

SN - 2073-4409

VL - 14

JO - Cells

JF - Cells

IS - 18

M1 - 1448

ER -