Weighing in on Adipogenesis

Nunn, Elizabeth R.; Shinde, Abhijit Babaji; Zaganjor, Elma

doi:10.3389/fphys.2022.821278

Cited by 14 publications

(12 citation statements)

References 78 publications

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“…In mammals, high-nutrient diets can drive the dramatic expansion of adipocyte cell size, termed hypertrophy, that enables them to absorb and store elevated nutrients as fat, thus avoiding lipotoxicity and ensuring metabolic homeostasis (Hansson et al, 2019; Virtue and Vidal-Puig, 2010). Dysfunctional hypertrophy is a recognized feature of diseases such as obesity and type 2 diabetes, but the mechanisms governing adipocyte cell size determination and expansion remain poorly understood (Nunn et al, 2022). In Drosophila , the central metabolic organ regulating energy storage and signaling is the fat body (FB), functionally analogous to the mammalian adipose tissue and liver (Arrese and Soulages, 2010; Musselman et al, 2013; Musselman and Kühnlein, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Dysfunctional hypertrophy is a recognized feature of diseases such as obesity and type 2 diabetes, but the mechanisms governing adipocyte cell size determination and expansion remain poorly understood (Nunn et al, 2022). In Drosophila, the central metabolic organ regulating energy storage and signaling is the fat body (FB), functionally analogous to the mammalian adipose tissue and liver (Arrese and Soulages, 2010;Musselman et al, 2013;Musselman and Kühnlein, 2018).…”

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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The fat body cortical actin network regulatesDrosophilainter-organ nutrient trafficking, signaling, and adipose cell size

Ugrankar

Tran

Bowerman

et al. 2022

Preprint

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Defective nutrient storage and adipocyte enlargement (hypertrophy) are emerging features of metabolic syndrome and type 2 diabetes. How the cytoskeletal network contributes to nutrient uptake, fat storage, and adipocyte size remain poorly understood. Utilizing the Drosophila larval fat body (FB) as a model adipose tissue, we show that a specific actin isoform—Act5C—forms the cortical actin network necessary for inter-organ lipid trafficking. Act5C also promotes FB tissue expansion during larval development so larvae can store sufficient biomass for metamorphosis. We find FB-specific loss of Act5C, but not other Drosophila actins, perturbs FB triglyceride (TG) storage in lipid droplets (LDs), resulting in developmentally delayed larvae that fail to develop into flies. Act5C localizes to the FB cell surface where it intimately contacts peripheral LDs (pLDs), forming a cortical actin network together with spectrins for cell architectural support. While both the cortical actin and spectrin cytoskeletons maintain FB cell surface architecture, we find that only the actin network is required for fat storage. Mechanistically, we show that FBs lacking the Act5C cortical cytoskeleton exhibit a block in lipoprotein (Lpp) secretion from FB cells, and a subsequent disruption of gut:FB inter-organ lipid transport, resulting in mid-gut fat accumulation. Utilizing temporal RNAi-depletion approaches, we also reveal that Act5C is indispensable post-embryogenesis during larval feeding to promote FB cell expansion. Act5C-deficient FBs fail to expand cell sizes, leading to lipodystrophic larvae unable to accrue sufficient biomass for metamorphosis. Collectively, we propose that the Act5C-mediated cortical actin network of Drosophila adipose tissue plays an essential role in post-embryonic inter-organ nutrient transport and FB cell size determination for organismal energy homeostasis and development.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The fat body cortical actin network regulatesDrosophilainter-organ nutrient trafficking, signaling, and adipose cell size

Ugrankar

Tran

Bowerman

et al. 2022

Preprint

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“…This process transforms fibroblast-like preadipocytes into differentiated (or mature) adipocytes filled with numerous lipid droplets (LDs) [11,12]. There is accumulating evidence that diverse adipogenic transcription factors, including CCAAT/enhancer-binding proteins (C/EBPs), peroxisome proliferator-activated receptors (PPARs), and signal transducer and activator of transcription (STAT) family proteins, play a key role in preadipocyte differentiation [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Anti-adipogenic and Pro-lipolytic Effects on 3T3-L1 Preadipocytes by CX-4945, an Inhibitor of Casein Kinase 2

Yadav

Jang

2022

IJMS

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Casein kinase 2 (CK2) is a ubiquitously expressed serine/threonine kinase and is upregulated in human obesity. CX-4945 (Silmitasertib) is a CK2 inhibitor with anti-cancerous and anti-adipogenic activities. However, the anti-adipogenic and pro-lipolytic effects and the mode of action of CX-4945 in (pre)adipocytes remain elusive. Here, we explored the effects of CX-4945 on adipogenesis and lipolysis in differentiating and differentiated 3T3-L1 cells, a murine preadipocyte cell line. CX-4945 at 15 μM strongly reduced lipid droplet (LD) accumulation and triglyceride (TG) content in differentiating 3T3-L1 cells, indicating the drug’s anti-adipogenic effect. Mechanistically, CX-4945 reduced the expression levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and perilipin A in differentiating 3T3-L1 cells. Strikingly, CX-4945 further increased the phosphorylation levels of cAMP-activated protein kinase (AMPK) and liver kinase B-1 (LKB-1) while decreasing the intracellular ATP content in differentiating 3T3-L1 cells. In differentiated 3T3-L1 cells, CX-4945 had abilities to stimulate glycerol release and elevate the phosphorylation levels of hormone-sensitive lipase (HSL), pointing to the drug’s pro-lipolytic effect. In addition, CX-4945 induced the activation of extracellular signal-regulated kinase-1/2 (ERK-1/2), and PD98059, an inhibitor of ERK-1/2, attenuated the CX4945-induced glycerol release and HSL phosphorylation in differentiated 3T3-L1 cells, indicating the drug’s ERK-1/2-dependent lipolysis. In summary, this investigation shows that CX-4945 has strong anti-adipogenic and pro-lipolytic effects on differentiating and differentiated 3T3-L1 cells, mediated by control of the expression and phosphorylation levels of CK2, C/EBP-α, PPAR-γ, FAS, ACC, perilipin A, AMPK, LKB-1, ERK-1/2, and HSL.

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“…Much like transcription and signaling events, metabolites regulate adipocyte differentiation ( 19 ). To induce adipogenesis, glucose generates NADPH, a cofactor critical for lipogenesis, through the pentose phosphate pathway ( 20 ).…”

mentioning

confidence: 99%

Inhibition of nucleotide biosynthesis disrupts lipid accumulation and adipogenesis

Shinde¹,

Nunn²,

Wilson³

et al. 2023

Journal of Biological Chemistry

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Weighing in on Adipogenesis

Cited by 14 publications

References 78 publications

The fat body cortical actin network regulatesDrosophilainter-organ nutrient trafficking, signaling, and adipose cell size

The fat body cortical actin network regulatesDrosophilainter-organ nutrient trafficking, signaling, and adipose cell size

Anti-adipogenic and Pro-lipolytic Effects on 3T3-L1 Preadipocytes by CX-4945, an Inhibitor of Casein Kinase 2

Inhibition of nucleotide biosynthesis disrupts lipid accumulation and adipogenesis

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