Abstract MP32: Diaphanous 1 Regulates Actin Polymerization In Adipocytes: Potential Mechanism Regulating Obesity In Mice
| Autor: | Henry H Ruiz, Ann Marie Schmidt |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 41 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | The underlying pathophysiological mechanisms of obesity, a hallmark of metabolic and cardiovascular diseases, are not fully elucidated. Adipocyte hypertrophy contributes to insulin resistance, and is coupled to meaningful alterations in actin dynamics that favor actin polymerization. Diaphanous 1 (Diaph1) is a formin protein that associates with the fast-growing/barded end of actin filaments to regulate actin dynamics. We hypothesized that deletion of Diaph1 or pharmacological regulation of actin polymerization in the context of lipid surplus would prevent obesity, decrease adipocyte lipid load and protect from obesity-associated metabolic disease. We modeled obesity by feeding wild type (Wt) mice and mice globally or with adipocyte-specific deletion of Diaph1 a high fat diet (60%kcal from fat). Body composition was assessed by Dual-energy X-ray absorptiometry (DEXA) and dynamic glucose and insulin tolerance testing was performed to assess metabolic state. In-vitro studies were carried out in adipocytes differentiated from primary pre-adipocytes or 3T3-L1 fibroblasts. Lipid overload was modeled using a mixture of palmitate/oleate (P/O). Actin manipulations were achieved by pharmacologically preventing (Latrunculin B [LatB]) or promoting (Jasplakinolide [Jasp]) F-actin polymerization. Mice globally devoid of, or with adipocyte specific Diaph1 deletion were protected from obesity, glucose intolerance and insulin resistance. Wt adipocytes treated with P/O exhibited pronounced accumulation of triglycerides (Tg) which was absent in adipocytes differentiated from Diaph1 knock out mice. Pharmacological studies in 3T3-L1-derived adipocytes confirmed the P/O-induced Tg accumulation which was prevented by LatB and exacerbated by Jasp. We present the novel finding that adipocyte DIAPH1 is a major player in the pathophysiology of obesity and associated metabolic sequela which results, at least in part, from regulation of adipocyte hypertrophy by preventing actin polymerization. Thus, we propose that actin remodeling is an underlying mechanism for adipocyte hypertrophy in obesity and inhibition of DIAPH1 may represent a potential therapeutic target for the treatment of obesity and related metabolic and cardiovascular disorders. |
| Databáze: | OpenAIRE |
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