Abstract
The phytotherapeutic protein stem bromelain (SBM) is used as an anti-obesity alternative medicine. We show at the cellular level that SBM irreversibly inhibits 3T3-L1 adipocyte differentiation by reducing adipogenic gene expression and induces apoptosis and lipolysis in mature adipocytes. At the molecular level, SBM suppressed adipogenesis by downregulating C/EBPα and PPARγ independent of C/EBPβ gene expression. Moreover, mRNA levels of adipocyte fatty acid-binding protein (ap2), fatty acid synthase (FAS), lipoprotein lipase (LPL), CD36, and acetyl-CoA carboxylase (ACC) were also downregulated by SBM. Additionally, SBM reduced adiponectin expression and secretion. SBM's ability to repress PPARγ expression seems to stem from its ability to inhibit Akt and augment the TNFα pathway. The Akt–TSC2–mTORC1 pathway has recently been described for PPARγ expression in adipocytes. In our experiments, TNFα upregulation compromised cell viability of mature adipocytes (via apoptosis) and induced lipolysis. Lipolytic response was evident by downregulation of anti-lipolytic genes perilipin, phosphodiestersae-3B (PDE3B), and GTP binding protein Giα1, as well as sustained expression of hormone sensitive lipase (HSL). These data indicate that SBM, together with all-trans retinoic-acid (atRA), may be a potent modulator of obesity by repressing the PPARγ-regulated adipogenesis pathway at all stages and by augmenting TNFα-induced lipolysis and apoptosis in mature adipocytes.
Highlights
Adipose tissue is crucial for energy storage and lipid homeostasis [1,2,3], but an imbalance between energy intake and expenditure leads to obesity, which is a major risk factor for many chronic diseases and metabolic disorders such as type 2 diabetes, hypertension, hyperlipidemia, and arteriosclerosis [4]
stem bromelain (SBM) inhibits 3T3-L1 adipocyte differentiation To investigate the effect of SBM on adipocyte differentiation, we first looked at the accumulation of intracellular lipids
SBM was added to cultures during the treatment with Dex and isobutyl methyl xanthine (IBMX), and it was maintained in the cultures when cells were switched to medium with fetal bovine serum and insulin alone
Summary
Adipose tissue is crucial for energy storage and lipid homeostasis [1,2,3], but an imbalance between energy intake and expenditure leads to obesity, which is a major risk factor for many chronic diseases and metabolic disorders such as type 2 diabetes, hypertension, hyperlipidemia, and arteriosclerosis [4]. Adipose tissue mass is determined by processes governing adipocyte size and number [6]. In the adipogenic differentiation program preadipocytes undergo mitotic clonal expansion (MCE): a process that differs from proliferation of nonconfluent adipocytes and is essential for adipocyte differentiation [8]. MCE is accompanied by induction of CCAAT/enhancer-binding protein (C/EBP) b and C/EBPd. During mid-phase adipocyte differentiation, the expression of CEBPa and PPARc, which are both antimitotic, occurs as the cells exit the cell cycle. During mid-phase adipocyte differentiation, the expression of CEBPa and PPARc, which are both antimitotic, occurs as the cells exit the cell cycle These proteins are thought to be terminating MCE [9,10]. Decreases in adipose tissue mass may involve the loss of lipids through lipolysis and the loss of mature fat cells through apoptosis [13]
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