Berberine modulates deacetylation of PPARγ to promote adipose tissue remodeling and thermogenesis via AMPK/SIRT1 pathway.
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ABSTRACT:
SUBMITTER: Xu Y
PROVIDER: S-EPMC8375237 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Brown adipose tissue (BAT) can disperse stored energy as heat. Promoting BAT-like features in white adipose (WAT) is an attractive, if elusive, therapeutic approach to staunch the current obesity epidemic. Here we report that gain of function of the NAD-dependent deacetylase SirT1 or loss of function of its endogenous inhibitor Deleted in breast cancer-1 (Dbc1) promote "browning" of WAT by deacetylating peroxisome proliferator-activated receptor (Ppar)-γ on Lys268 and Lys293. SirT1-dependent deacetylation of Lys268 and Lys293 is required to recruit the BAT program coactivator Prdm16 to Pparγ, leading to selective induction of BAT genes and repression of visceral WAT genes associated with insulin resistance. An acetylation-defective Pparγ mutant induces a brown phenotype in white adipocytes, whereas an acetylated mimetic fails to induce "brown" genes but retains the ability to activate "white" genes. We propose that SirT1-dependent Pparγ deacetylation is a form of selective Pparγ modulation of potential therapeutic import.
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Project description:Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of adenosine triphosphate (ATP) synthase. Here, we provide evidence that phosphatidylethanolamine (PE) modulates UCP1-dependent proton conductance across the IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist-induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PE-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.
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Project description:Atherosclerosis is a chronic inflammatory disease that commonly affects the elderly and is characterized by vascular damage, macrophage infiltration, and plaque formation. Moreover, it increases the risk of cardiovascular disease. The pathogenesis of atherosclerosis involves an interplay between macrophage autophagy and apoptosis. A recently discovered transcription factor, transcription factor EB (TFEB) is known to activate autophagy in macrophages. Sirtuin deacetylase 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, activates several transcription factors, including TFEB. We studied the effects of berberine on the NAD+ synthesis pathway and interactions between SIRT1 and TFEB. We also studied the effects of berberine-induced TFEB activation via SIRT1 on autophagy and apoptosis of peritoneal macrophages. We found that berberine promoted autophagy of peritoneal macrophages by activating SIRT1 via the NAD+ synthesis pathway and, in turn, promoting TFEB nuclear translocation and deacetylation. The functional regulation of SIRT1 and TFEB by berberine could be exploited as a potential therapeutic strategy for atherosclerosis.
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Project description:Estrogens play a major role in the modulation of energy balance through central and peripheral actions. Here, we demonstrate that central action of estradiol (E2) inhibits AMP-activated protein kinase (AMPK) through estrogen receptor alpha (ERα) selectively in the ventromedial nucleus of the hypothalamus (VMH), leading to activation of thermogenesis in brown adipose tissue (BAT) through the sympathetic nervous system (SNS) in a feeding-independent manner. Genetic activation of AMPK in the VMH prevented E2-induced increase in BAT-mediated thermogenesis and weight loss. Notably, fluctuations in E2 levels during estrous cycle also modulate this integrated physiological network. Together, these findings demonstrate that E2 regulation of the VMH AMPK-SNS-BAT axis is an important determinant of energy balance and suggest that dysregulation in this axis may account for the common changes in energy homeostasis and obesity linked to dysfunction of the female gonadal axis.
| S-EPMC4082097 | biostudies-literature
Project description:Interplay between parenchymal energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of cellular origin or specialized niche, adipocytes require the activity of the nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ) for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ, however, the molecular mechanisms by which PPARγ licenses white adipose tissue (WAT) to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ-long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity (DIO). Pharmacologic inhibition or genetic deletion of the lncRNA Lexis, enhances UCP-1 dependent and independent thermogenesis. Adipose tissue specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT signaling that preserves white adipose tissue plasticity.
2023-09-27 | GSE216272 | GEO
Project description:BackgroundBerberine effectively alleviates non-alcoholic fatty liver disease (NAFLD). Nevertheless, the mechanism is incompletely comprehended. It has been reported that SIRT1 mediates lipid metabolism in liver and berberine promotes the expression of SIRT1 in hepatocytes. We hypothesized that SIRT1 mediated the effect of berberine on NAFLD.MethodsThe effects of berberine on NAFLD were evaluated in C57BL/6J mice fed a high-fat diet (HFD) and in mouse primary hepatocytes and cell lines exposed to palmitate. The change of fatty acid oxidation (FAO) and the activity of CPT1A were observed in HepG2 cells. Quantitative real-time polymerase chain reaction and Western blot were employed to observe the expression of SIRT1 and lipid metabolism-related molecules. The interaction between SIRT1 and CPT1A was investigated by using co-immunoprecipitation assay in HEK293T cells.ResultsBerberine treatment attenuated hepatic steatosis, reduced triglyceride (190.1 ± 11.2 μmol/g liver vs 113.6 ± 7.6 μmol/g liver, P < 0.001) and cholesterol (11.3 ± 2.5 μmol/g liver vs 6.3 ± 0.4 μmol/g liver, P < 0.001) concentration in the liver, and improved lipid and glucose metabolism disorders compared with the HFD group. The expression of SIRT1 was reduced in the liver of NAFLD patients and mouse models. Berberine increased the expression of SIRT1 and promoted the protein level of CPT1A and its activity in HepG2 cells. SIRT1 overexpression mimicked the effect of berberine on reducing triglyceride levels in HepG2 cells, whereas SIRT1 knock-down attenuated the effect of berberine. Mechanistically, berberine increased the expression of SIRT1. SIRT1 deacetylated CPT1A at the Lys675 site, which suppressed its ubiquitin-dependent degradation, thereby promoting FAO and alleviating non-alcoholic liver steatosis.ConclusionsBerberine promoted SIRT1 deacetylation of CPT1A at the Lys675 site, which reduced the ubiquitin-dependent degradation of CPT1A and ameliorated non-alcoholic liver steatosis.
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Project description:Phosphocholine phosphatase-1 (PHOSPHO1) is a phosphocholine phosphatase that catalyzes the hydrolysis of phosphocholine (PC) to choline. Here we demonstrate that the PHOSPHO1 transcript is highly enriched in mature brown adipose tissue (BAT) and is further induced by cold and isoproterenol treatments of BAT and primary brown adipocytes. In defining the functional relevance of PHOPSPHO1 in BAT thermogenesis and energy metabolism, we show that PHOSPHO1 knockout mice are cold-tolerant, with higher expression of thermogenic genes in BAT, and are protected from high-fat diet-induced obesity and development of insulin resistance. Treatment of mice with the PHOSPHO1 substrate phosphocholine is sufficient to induce cold tolerance, thermogenic gene expression, and allied metabolic benefits. Our results reveal a role of PHOSPHO1 as a negative regulator of BAT thermogenesis, and inhibition of PHOSPHO1 or enhancement of phosphocholine represent innovative approaches to manage the metabolic syndrome.
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Project description:Berberine (BBR), which is an active component of Coptis chinensis Franch, has been reported to improve glucose metabolism and insulin resistance in animal and human studies, predominantly via activation of the 5'-adenosine monophosphate kinase (AMPK) pathway and suppression of the inflammation response. However, the mechanisms underlying the effects of BBR on AMPK and inflammation remain unclear. In this present study, we found that BBR upregulated SIRT1 expression in 3T3L-1 adipocytes and adipose tissue. Inhibition of SIRT1 blunted the BBR-induced increase in glucose consumption and uptake in adipocytes. The BBR-induced activation of the AMPK pathway and AKT phosphorylation in adipocytes and adipose tissue were also attenuated by inhibition or knockout of Sirt1. The BBR-induced improvement of systemic insulin sensitivity was impaired by Sirt1 knockout in HFD-induced obese mice. The suppressing effects of BBR on systemic and local inflammatory responses, such as serum concentrations and expression of inflammatory cytokines, phosphorylation of c-Jun N-terminal kinase (JNK) and IKKβ, and the accumulation of F4/80-positive macrophages in adipose tissue were also attenuated in Sirt1 knockout mice. The BBR-induced decrease in PGC-1α acetylation was reversed by inhibition or knockout of Sirt1 in adipocytes and adipose tissue. Together, these results indicate that adipose tissue SIRT1 is a key regulator of the insulin sensitizing and anti-inflammatory effects of BBR, which contributes to the improvement of metabolic dysregulation.
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Project description:Interplay between parenchymal energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of cellular origin or specialized niche, adipocytes require the activity of the nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ) for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ, however, the molecular mechanisms by which PPARγ licenses white adipose tissue (WAT) to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ-long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity (DIO). Pharmacologic inhibition or genetic deletion of the lncRNA Lexis, enhances UCP-1 dependent and independent thermogenesis. Adipose tissue specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT signaling that preserves white adipose tissue plasticity.
2023-09-27 | GSE216608 | GEO
Project description:Obesity occurs when excess energy accumulates in white adipose tissue (WAT), whereas brown adipose tissue (BAT), which is specialized in dissipating energy through thermogenesis, potently counteracts obesity. White adipocytes can be converted to thermogenic "brown-like" cells (beige cells; WAT browning) under various stimuli, such as cold exposure. AMP-activated protein kinase (AMPK) is a crucial energy sensor that regulates energy metabolism in multiple tissues. However, the role of AMPK in adipose tissue function, especially in the WAT browning process, is not fully understood. To illuminate the effect of adipocyte AMPK on energy metabolism, we generated Adiponectin-Cre-driven adipose tissue-specific AMPK α1/α2 KO mice (AKO). These AKO mice were cold intolerant and their inguinal WAT displayed impaired mitochondrial integrity and biogenesis, and reduced expression of thermogenic markers upon cold exposure. High-fat-diet (HFD)-fed AKO mice exhibited increased adiposity and exacerbated hepatic steatosis and fibrosis and impaired glucose tolerance and insulin sensitivity. Meanwhile, energy expenditure and oxygen consumption were markedly decreased in the AKO mice both in basal conditions and after stimulation with a β3-adrenergic receptor agonist, CL 316,243. In contrast, we found that in HFD-fed obese mouse model, chronic AMPK activation by A-769662 protected against obesity and related metabolic dysfunction. A-769662 alleviated HFD-induced glucose intolerance and reduced body weight gain and WAT expansion. Notably, A-769662 increased energy expenditure and cold tolerance in HFD-fed mice. A-769662 treatment also induced the browning process in the inguinal fat depot of HFD-fed mice. Likewise, A-769662 enhanced thermogenesis in differentiated inguinal stromal vascular fraction (SVF) cells via AMPK signaling pathway. In summary, a lack of adipocyte AMPKα induced thermogenic impairment and obesity in response to cold and nutrient-overload, respectively, whereas chronic AMPK activation by A-769662 promoted WAT browning in inguinal WAT and protected against HFD-induced obesity and related metabolic dysfunction. These findings reveal a vital role for adipocyte AMPK in regulating the browning process in inguinal WAT and in maintaining energy homeostasis, which suggests that the targeted activation of adipocyte AMPK may be a promising strategy for anti-obesity therapy.
| S-EPMC5826329 | biostudies-literature