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Distinct functions of PPAR? isoforms in regulating adipocyte plasticity.

ABSTRACT: A better understanding of the mechanisms underlying obesity and its comorbidities is key to designing new therapies and treatments. PPAR? is a master regulator of adipocyte biology but the functions of its isoforms are poorly distinguished. Here we demonstrated that PPAR?1 is preferentially expressed in catabolic fat depots while PPAR?2 presents itself at a higher level in browning-resistant depots. PPAR?2, but not PPAR?1, responds to endogenous ligands to induce adipogenesis, and the isoforms regulate distinct sets of white and brown adipocyte genes. Moreover, PPAR?1 negatively correlates while PPAR?2 positively correlates with adiposity in human subcutaneous and visceral fat. These results together indicate that PPAR?1 and PPAR?2 have distinct functions in regulating adipocyte plasticity, and future research should take into account the binary roles of both isoforms in order to identify druggable gene targets and pathways relevant for treatment of metabolic disorders.

SUBMITTER: Li D

PROVIDER: S-EPMC5147489 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Distinct functions of PPARγ isoforms in regulating adipocyte plasticity.

Li Dylan D Zhang Feng F Zhang Xuan X Xue Chenyi C Namwanje Maria M Fan Lihong L Reilly Muredach P MP Hu Fang F Qiang Li L

Biochemical and biophysical research communications 20161103 1-2

A better understanding of the mechanisms underlying obesity and its comorbidities is key to designing new therapies and treatments. PPARγ is a master regulator of adipocyte biology but the functions of its isoforms are poorly distinguished. Here we demonstrated that PPARγ1 is preferentially expressed in catabolic fat depots while PPARγ2 presents itself at a higher level in browning-resistant depots. PPARγ2, but not PPARγ1, responds to endogenous ligands to induce adipogenesis, and the isoforms r ...[more]

PMID: 27818196

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Project description:BACKGROUND:AKT, also known as protein kinase B, is a key element of the PI3K/AKT signaling pathway. Moreover, AKT regulates the hallmarks of cancer, e.g. tumor growth, survival and invasiveness of tumor cells. After AKT was discovered in the early 1990s, further studies revealed that there are three different AKT isoforms, namely AKT1, AKT2 and AKT3. Despite their high similarity of 80%, the distinct AKT isoforms exert non-redundant, partly even opposing effects under physiological and pathological conditions. Breast cancer as the most common cancer entity in women, frequently shows alterations of the PI3K/AKT signaling. MAIN CONTENT:A plethora of studies addressed the impact of AKT isoforms on tumor growth, metastasis and angiogenesis of breast cancer as well as on therapy response and overall survival in patients. Therefore, this review aimed to give a comprehensive overview about the isoform-specific effects of AKT in breast cancer and to summarize known downstream and upstream mechanisms. Taking account of conflicting findings among the studies, the majority of the studies reported a tumor initiating role of AKT1, whereas AKT2 is mainly responsible for tumor progression and metastasis. In detail, AKT1 increases cell proliferation through cell cycle proteins like p21, p27 and cyclin D1 and impairs apoptosis e.g. via p53. On the downside AKT1 decreases migration of breast cancer cells, for instance by regulating TSC2, palladin and EMT-proteins. However, AKT2 promotes migration and invasion most notably through regulation of β-integrins, EMT-proteins and F-actin. Whilst AKT3 is associated with a negative ER-status, findings about the role of AKT3 in regulation of the key properties of breast cancer are sparse. Accordingly, AKT1 is mutated and AKT2 is amplified in some cases of breast cancer and AKT isoforms are associated with overall survival and therapy response in an isoform-specific manner. CONCLUSIONS:Although there are several discussed hypotheses how isoform specificity is achieved, the mechanisms behind the isoform-specific effects remain mostly unrevealed. As a consequence, further effort is necessary to achieve deeper insights into an isoform-specific AKT signaling in breast cancer and the mechanism behind it.

Dataset Information

Distinct functions of PPAR? isoforms in regulating adipocyte plasticity.

Publications

Distinct functions of PPARγ isoforms in regulating adipocyte plasticity.

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