Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice

Xie, Bingxian; Murali, Anjana; Vandevender, Amber M.; Chen, Jeffrey; Silva, Agustin Gil; Bello, Fiona M.; Chuan, Byron; Bahudhanapati, Harinath; Sipula, Ian; Dedousis, Nikolaos; Shah, Faraaz; O’Donnell, Christopher P.; Alder, Jonathan K.; Jurczak, Michael J.

doi:10.1016/j.isci.2022.105569

Cited by 13 publications

(6 citation statements)

References 39 publications

(68 reference statements)

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“…We generated a murine model of hepatocyte‐specific senescence using adenovirus‐delivered Cre recombinase and biallelic Trf2 F/F mice (Figure 4a ). A liver‐focused model was chosen given the significant existing literature on hepatic mitochondrial isolation and respiratory studies (Chance & Williams, 1955 ; Edmunds et al, 2020 ; Frezza et al, 2007 ; Hogeboom et al, 1948 ), ease of viral targeting (Russell et al, 2019 ; Xie et al, 2022 ), and known tolerance of TRF2 deletion in this tissue (Lazzerini Denchi et al, 2006 ). Additionally, as a highly metabolically active tissue, we reasoned that our ability to detect differences between control and senescent tissues would be greater.…”

Section: Resultsmentioning

confidence: 99%

Intact mitochondrial function in the setting of telomere‐induced senescence

Sullivan,

Bello,

Silva

et al. 2023

Aging Cell

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Mitochondria play essential roles in metabolic support and signaling within all cells. Congenital and acquired defects in mitochondria are responsible for several pathologies, including premature entrance to cellar senescence. Conversely, we examined the consequences of dysfunctional telomere‐driven cellular senescence on mitochondrial biogenesis and function. We drove senescence in vitro and in vivo by deleting the telomere‐binding protein TRF2 in fibroblasts and hepatocytes, respectively. Deletion of TRF2 led to a robust DNA damage response, global changes in transcription, and induction of cellular senescence. In vitro, senescent cells had significant increases in mitochondrial respiratory capacity driven by increased cellular and mitochondrial volume. Hepatocytes with dysfunctional telomeres maintained their mitochondrial respiratory capacity in vivo, whether measured in intact cells or purified mitochondria. Induction of senescence led to the upregulation of overlapping and distinct genes in fibroblasts and hepatocytes, but transcripts related to mitochondria were preserved. Our results support that mitochondrial function and activity are preserved in telomere dysfunction‐induced senescence, which may facilitate continued cellular functions.

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Section: Resultsmentioning

confidence: 99%

Intact mitochondrial function in the setting of telomere‐induced senescence

Sullivan,

Bello,

Silva

et al. 2023

Aging Cell

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“…To evaluate the activity of the synthesized compounds ( Scheme 1 A–C) in increasing GDF15 expression, we incubated Huh-7 human hepatic cells with the new compounds (30 µM) for 24 h, using metformin (5 mM) and BC1618 (30 µM) as standards for comparison purposes. Hepatic cells were used since circulating GDF15 is primarily derived from the liver [ 17 ]. As shown in Table 1 , metformin caused a 2.7-fold increase in GDF15 mRNA levels compared with control cells.…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of AMPK Activators and GDF15 Inducers

et al. 2023

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Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, BC1618. This molecule showed a better potency than metformin, increasing GDF15 mRNA levels in human Huh-7 hepatic cells. Based on BC1618, structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound 21 showed a higher increase in GDF15 mRNA levels compared with BC1618. Metformin, BC1618, and compound 21 increased phosphorylated AMPK, but only 21 increased GDF15 protein levels. Overall, these findings indicate that 21 has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and BC1618.

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“…Given that a role in promoting lipid oxidation has also been attributed to GDF15 ( 50 ), it is possible that the two molecules could have a synergic role in the skeletal muscle. As far as Insulin, it is known that GDF15 improves insulin sensitivity ( 51 , 52 ), thus it is possible that an inverse correlation exists between Insulin and GDF15. However, it is to note that existing data regard c-GDF15, but not SM-GDF15, therefore this hypothesis has to be further validated.…”

Section: Discussionmentioning

confidence: 99%

Different roles of circulating and intramuscular GDF15 as markers of skeletal muscle health

Chiariello,

Conte,

Rossetti

et al. 2024

Front. Endocrinol.

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IntroductionGrowth Differentiation Factor 15 (GDF15) is a mitokine expressed in response to various stresses whose circulating levels increase with age and are associated with numerous pathological conditions, including muscle wasting and sarcopenia. However, the use of circulating GDF15 (c-GDF15) as a biomarker of sarcopenia is still debated. Moreover, the role of GDF15 intracellular precursor, pro-GDF15, in human skeletal muscle (SM-GDF15) is not totally understood. In order to clarify these points, the association of both forms of GDF15 with parameters of muscle strength, body composition, metabolism and inflammation was investigated.Methodsthe levels of c-GDF15 and SM-GDF15 were evaluated in plasma and muscle biopsies, respectively, of healthy subjects (HS) and patients with lower limb mobility impairment (LLMI), either young (<40 years-old) or old (>70 years-old). Other parameters included in the analysis were Isometric Quadriceps Strength (IQS), BMI, lean and fat mass percentage, Vastus lateralis thickness, as well as circulating levels of Adiponectin, Leptin, Resistin, IGF-1, Insulin, IL6, IL15 and c-PLIN2. Principal Component Analysis (PCA), Canonical Discriminant Analysis (CDA) and Receiving Operating Characteristics (ROC) analysis were performed.Resultsc-GDF15 but not SM-GDF15 levels resulted associated with decreased IQS and IGF-1 levels in both HS and LLMI, while only in LLMI associated with increased levels of Resistin. Moreover, in LLMI both c-GDF15 and SM-GDF15 levels were associated with IL-6 levels, but interestingly SM-GDF15 is lower in LLMI with respect to HS. Furthermore, a discrimination of the four groups of subjects based on these parameters was possible with PCA and CDA. In particular HS, LLMI over 70 years or under 40 years of age were discriminated based on SM-GDF15, c-GDF15 and Insulin levels, respectively.Conclusionour data support the idea that c-GDF15 level could be used as a biomarker of decreased muscle mass and strength. Moreover, it is suggested that c-GDF15 has a different diagnostic significance with respect to SM-GDF15, which is likely linked to a healthy and active state.

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Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice

Cited by 13 publications

References 39 publications

Intact mitochondrial function in the setting of telomere‐induced senescence

Intact mitochondrial function in the setting of telomere‐induced senescence

Design and Synthesis of AMPK Activators and GDF15 Inducers

Different roles of circulating and intramuscular GDF15 as markers of skeletal muscle health

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