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  • American Diabetes Association  (3)
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  • American Diabetes Association  (3)
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  • 1
    Online Resource
    Online Resource
    1625-P: Osteoprotection by FNIP1 Signaling in Skeletal Muscle
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-20)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: Obesity is increasingly recognized to exert negative impact on bone mass. Skeletal muscle and bone are closely related throughout life, and muscle dysfunction can cause osteoporosis. Understanding of the crosstalk between muscle and bone could have implications for maintaining bone fitness in various disease states such as obesity. FNIP1 is emerging as key regulator of muscle metabolism acting via AMPK. However, the role of muscle FNIP1 in bone mass control is unknown. Using both gain- and loss-of function muscle-specific genetic models, we show that in addition to the known role in the regulation of mitochondrial function muscle fiber type, FNIP1 participates in muscle programs that govern bone homeostasis. FNIP1 KO mice showed a decrease in trabecular bone volume and bone mineral density, whereas muscle specific restoration of FNIP1 expression in KO mice (FNIP1Tg/KO) reversed the bone loss phenotypes. Femoral bending tests revealed a marked decrease in elastic modulus and maximum force in FNIP1 KO mice but increase in FNIP1 TgKO mice. Consistent with these findings, muscle cell-specific deletion of FNIP1 resulted in a pronounced bone structural and mechanical dysfunction. Using AMPKα1/α2 KO lines, we show that muscle FNIP1 exerts control actions upon bone homeostasis independently of AMPK. Through comprehensive RNA-seq and genomic analyses, we reveal that muscle FNIP1 deficiency induces IGF2 secretion, thereby driving an IGF2-depenent osteoclast program. Importantly, we also found that the muscle FNIP1-IGF2 regulatory circuit is associated with osteoporosis in humans. Thus, muscle FNIP1 is a critical safeguard of bone mass. These findings provide new therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and musculoskeletal diseases. Disclosure M.Yan: None. Z.Xu: None. Y.Yin: None. T.Fu: None. Z.Zhou: None. L.Yang: None. Z.Gan: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-1625-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
    detail.hit.zdb_id: 1501252-9
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  • 2
    Online Resource
    Online Resource
    75-OR: Cold-Responsive Proteolytic Rewiring of Mitochondria Safeguards White Fat Thermogenic Remodeling
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-20)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity acting both as protein quality surveillance and regulatory enzymes. It remains unclear, however, whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switch such as white-to-beige conversion of adipocytes. Here we report that cold-responsive mitochondrial proteolysis is a prerequisite for conversion from white-to-beige adipocytes during white adipose tissue (WAT) browning. MitoTimer reporter and chemical thiol probe analysis reveal that thermogenic stimulation selectively promotes mitochondrial proteostasis in WAT via mitochondrial protease LONP1 both in vivo and in vitro. Disruption of LONP1-dependent proteolysis substantially impairs cold or b3-AR agonist induced adipocyte identity programming, evidenced by the remarkably attenuated formation of UCP1+ multilocular adipocytes in IWAT from Lonp1 f/f/Adipoq-Cre (LONP1 AKO) mice. LONP1 AKO mice exposed to cold had lower body temperature, elevated serum TG and FFA levels. Chow-fed LONP1 AKO mice also developed glucose intolerance. “AdipoChaser” system “pulse-chase” lineage tracing experiments confirm that LONP1 ablation markedly blocks the direct cell fate programming of pre-existing mature adipocytes. Importantly, augmented LONP1 expression corrects aging-related impairments in white-to-beige adipocytes conversion. 10-month-old adipocyte-specific Lonp1 overexpression mice had significantly lower body weight and fat mass as a result of elevated energy expenditure. Thus, the identification of LONP1 as a critical safeguard of WAT beiging holds promise for translational applications in enhancing white-to-beige adipocytes conversion capacity relevant to a variety of metabolic disease states and during aging. Disclosure T.Fu: None. W.Sun: None. Z.Zhou: None. Z.Xu: None. M.Yan: None. L.Yang: None. Y.Yin: None. Z.Gan: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-75-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
    detail.hit.zdb_id: 1501252-9
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  • 3
    Online Resource
    Online Resource
    166-OR: AMPK-Dependent Regulation of Skeletal Muscle Mitochondrial Function by FNIP1
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Skeletal muscle mitochondria are essential for maintaining metabolic homeostasis in response to a myriad of physiologic or pathophysiological stresses. The folliculin (FLCN)-interacting protein 1 (FNIP1) forms a complex with AMP-activated protein kinase (AMPK), and we previously demonstrated that FNIP1 inhibits AMPK activity in myocytes. Using gain- and loss-of-function approaches in mice, we discovered that FNIP1 is necessary, but not sufficient, to suppress AMPK-dependent mitochondrial function in skeletal muscle. Muscles in FNIP1 knockout (KO) mice show enhanced red coloration, oxidative mitochondrial activity, and type I fiber transformation. Surprisingly, no change in mitochondrial oxidative capacity and fiber type switching was observed in transgenic mice overexpressing FNIP1 in muscle (FNIP1Tg), while restoration of the expression of FNIP1 in the KO muscle (FNIP1Tg/KO) reversed the mitochondrial oxidative metabolism program. RNA-seq profiling revealed that 3328 genes showed over 1.5-fold altered in FNIP1 KO muscle, and the majority number (2856) was regulated in a FNIP1-dependent manner. Gene ontology based analysis revealed that the primary FNIP1-altered genes were mitochondrial metabolic genes. Mitochondrial respiration analysis confirmed that both pyruvate- and succinate-driven state 3 respiration rates were significantly higher in FNIP1 KO muscle, whereas restoration of the expression of FNIP1 in KO muscle reduced the mitochondrial function. Importantly, AMPK, but not mTOR, was markedly induced in FNIP1 KO muscle but reduced in FNIP1Tg/KO muscle. Muscle-specific knockout of the two AMPKα subunits (AMPKα1α2 dmKO) reduced mitochondrial function in FNIP1 KO muscle. Similar results were obtained in skeletal myocytes in culture, using AMPK loss-of-function approaches in FNIP1 KO myocyte. Thus, FNIP1 represents a previously unrecognized negative regulator of muscle mitochondrial function and AMPK is vital for FNIP1 actions in skeletal muscle. Disclosure L. Xiao: None. J. Liu: None. Z. Sun: None. Y. Yin: None. Y. Mao: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-166-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
    detail.hit.zdb_id: 1501252-9
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