HDAC obesity

The mechanisms underlying glucocorticoid (GC)-induced obesity are poorly understood. Macrophages are the primary targets by which GCs exert pharmacological effects and perform critical functions in adipose tissue homeostasis. Here, we show that macrophages are essential for GC-induced obesity. Dexamethasone (Dex) strongly induced Krüppel-like factor 9 (Klf9) expression in macrophages. Similar to Dex, lentivirus-mediated Klf9 overexpression inhibits M1 and M2a markers expression, causing macrophage deactivation...

Generally, fasting and refeeding confer anti- and pro-inflammatory effects, respectively. In humans, these caloric-load interventions function, in part, via regulation of CD4+ T cell biology. However, mechanisms orchestrating this regulation remain incomplete. We employed integrative bioinformatics of RNA-seq and HPLC-mass spectrometry data to measure serum metabolites and gene expression of peripheral blood mononuclear cells isolated from fasting and refeeding in volunteers to identify nutrient-load metabolite-driven immunoregulation...

Short-chain fatty acids (SCFAs) are a subset of fatty acids that play crucial roles in maintaining normal physiology and developing metabolic diseases, such as obesity, diabetes, cardiovascular disease, and liver disease. Even though dairy products and vegetable oils are the direct dietary sources of SCFAs, their quantities are highly restricted. SCFAs are produced indirectly through microbial fermentation of fibers. The biological roles of SCFAs in human health and metabolic diseases are mainly due to their receptors, GPR41 and GPR43, FFAR2 and FFAR3...

Stem cells are a keystone of intestinal homeostasis, but their function could be shifted during energy imbalance or by crosstalk with microbial metabolites in the stem cell niche. This study reports the effect of obesity and microbiota-derived short-chain fatty acids (SCFAs) on intestinal stem cell (ISC) fate in human crypt-derived intestinal organoids (enteroids). ISC fate decision was impaired in obesity, resulting in smaller enteroids with less outward protruding crypts. Our key finding is that SCFAs switch ISC commitment to the absorptive enterocytes, resulting in reduced intestinal permeability in obese enteroids...

Obesity, with complications such as type 2 diabetes, dyslipidemia, and even cancer, is rampant worldwide. Histone deacetylases (HDACs) have been extensively studied as key players in the epigenetic regulation of cellular metabolism. However, the function of HDAC11 has long been focused on the immune and nervous systems and cancer development, and its potential role in obesity has been poorly studied. We found that the expression of HDAC11 was highly upregulated in the white adipose tissue (WAT) of obese mice and was closely related to the progression of obesity...

Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism. This metabolic reprogramming was also associated with impaired apoptosis and ferroptosis responses, and preserved muscle cell viability in response to lipotoxicity...

CARD9, a scaffolding protein, has been implicated in the pathogenesis of metabolic diseases, including obesity and diabetes. We recently reported novel roles for CARD9 in islet β-cell dysregulation under duress of gluco (HG)- and glucolipotoxic (GLT) stress. CARD9 expression was also increased in β-cells following exposure to HG and GLT stress. The current study is aimed at understanding the putative roles of histone deacetylation in HG- and GLT-induced expression of CARD9. Using two structurally distinct inhibitors of histone deacetylases (HDACs), namely trichostatin (TSA) and suberoylanilide hydroxamic acid (SAHA), we provide the first evidence to suggest that the increased expression of CARD9 seen under duress of HG and GLT stress is under the regulatory control of histone deacetylation...

SCOPE: Histone deacetylases (HDACs) play a crucial role in the transcriptional regulation of various genes which can contribute to metabolic disorders. Although sulforaphane (SFN), a natural HDAC inhibitor, has been reported to alleviate obesity in humans and mice, the specific mechanisms and how HDACs contribute to SFN's anti-obesity effects remain unclear. METHODS AND RESULTS: Oral administration of SFN in mice fed high-fat diet increases peroxisome proliferator activating receptor γ coactivator (PGC1α)-induced mitochondrial biogenesis in skeletal muscle...

BACKGROUND: Obesity is a multifactorial disease with epigenetic manifestations that increases the prevalence of associated comorbidities such as metabolic syndrome, cardiovascular dysfunction, and major depression disorder. Given the aforementioned, a search for new pharmacological alternatives for the treatment of this disease is necessary. The current study aimed to evaluate the effects of histone deacetylase-3 (HDAC3) inhibition caused by RGFP966 (a benzamide-type HDAC inhibitor selective for HDAC3) administration, in an animal model of obesity induced by high-fat diet (HFD)...

Obesity, one of the most serious public health issues, is caused by the imbalance of energy intake and energy expenditure. Increasing energy expenditure via induction of adipose tissue browning has become an appealing strategy to treat obesity and associated metabolic complications. Histone modifications have been confirmed to regulate cellular energy metabolism. Their biochemical mechanism of thermogenesis in adipose tissue, however, is incompletely understood. Herein, we report that class I histone deacetylases (HDAC) inhibitor MS275 increased PGC1α/UCP1 protein levels in inguinal white adipose tissue (iWAT) concomitant with elevated energy expenditure, reduced obesity and ameliorated glucose tolerance compared to control littermates...

The multiple beneficial effects of the short-chain fatty acid (SCFA) butyrate on human health, produced from fermentable carbohydrates by gut microbiota in the colon, are well known. At the intestinal level, butyrate regulates metabolism, helps in the transepithelial transport of fluids, inhibits inflammation, and induces the epithelial defense barrier. The liver receives a large amount of SCFAs along with the blood that travels from the gut via the portal vein. In many recent studies, butyrate has been reported to help prevent NAFLD, NASH, inflammation, cancer, and liver injuries...

The International Agency for Research on Cancer determined that obesity is the primary preventable cause of breast cancer. The nuclear receptor peroxisome proliferator activated receptor γ (PPARγ) binds inflammatory mediators in obesity and its expression is reduced in human breast cancer. We created a new model to better understand how the obese microenvironment alters nuclear receptor function in breast cancer. The obesity related cancer phenotype was PPARγ dependent; deletion of PPARγ in mammary epithelium which is a tumor suppressor in lean mice unexpectedly increased tumor latency, reduced the luminal progenitor (LP) tumor cell fraction, and increased autophagic and senescent cells...

OBJECTIVE: Norepinephrine stimulates the adipose tissue thermogenic program through a β-adrenergic receptor (βAR) - cyclic adenosine monophosphate (cAMP) - protein kinase A (PKA) signaling cascade. We discovered that a noncanonical activation of the mechanistic target of rapamycin complex 1 (mTORC1) by PKA is required for the βAR-stimulation of adipose tissue browning. However, the downstream events triggered by PKA-phosphorylated mTORC1 activation that drive this thermogenic response are not well understood...

Heart failure (HF) represents a group of complex clinical syndromes with high morbidity and mortality and has a significant global health burden. Inflammation and metabolic disorders are closely related to the development of HF, which are complex and depend on the severity and type of HF and common metabolic comorbidities such as obesity and diabetes. An increasing body of evidence indicates the importance of short-chain fatty acids (SCFAs) in regulating cardiac function. In addition, SCFAs represent a unique class of metabolites and play a distinct role in shaping systemic immunity and metabolism...

High-fat diet (HFD)-induced obesity is a cause of resistant hypertension. We have shown a possible link between histone deacetylases (HDACs) and renal angiotensinogen (Agt) upregulation in the HFD-induced hypertension, whereas the underlying mechanisms remain to be elucidated. Here, using a HDAC1/2 inhibitor romidepsin (FK228) and siRNAs, we determined roles of HDAC1 and HDAC2 in HFD-induced hypertension and found the pathologic signaling axis between HDAC1 and Agt transcription. Treatment with FK228 canceled the increased blood pressure of male C57BL/6 mice induced by HFD...

Brown and beige adipose tissues regulate body energy expenditure through adaptive thermogenesis, which converts energy into heat by oxidative phosphorylation uncoupling. Although promoting adaptive thermogenesis has been demonstrated to be a prospective strategy for obesity control, there are few methods for increasing adipose tissue thermogenesis in a safe and effective way. Histone deacetylase (HDAC) is a category of epigenetic modifying enzymes that catalyzes deacetylation on both histone and non-histone proteins...

BACKGROUND/OBJECTIVES: Hyperglycemia is a major cause of diabetes and diabetes-related diseases. Sodium butyrate (NaB) is a short-chain fatty acid derivative that produces dietary fiber by anaerobic bacterial fermentation in the large intestine and occurs in foods, such as Parmesan cheese and butter. Butyrate has been shown to prevent obesity, improve insulin sensitivity, and ameliorate dyslipidemia in diet-induced obese mice. Therefore, this study examined the effects and mechanism of NaB on the secretion of inflammatory cytokines induced by high glucose (HG) in THP-1 cells...

BACKGROUND: The prevalence of type 2 diabetes has dramatically increased in the past years. Increasing evidence supports that blood DNA methylation, the best studied epigenetic mark, is related to diabetes risk. Few prospective studies, however, are available. We studied the association of blood DNA methylation with diabetes in the Strong Heart Study. We used limma, Iterative Sure Independence Screening and Cox regression to study the association of blood DNA methylation with fasting glucose, HOMA-IR and incident type 2 diabetes among 1312 American Indians from the Strong Heart Study...

Studies in human microbiota dysbiosis have shown that short-chain fatty acids (SCFAs) like propionate, acetate, and particularly butyrate, positively affect energy homeostasis, behavior, and inflammation. This positive effect can be demonstrated in the reduction of butyrate-producing bacteria observed in the gut microbiota of individuals with type 2 diabetes (T2DM) and other energy-associated metabolic alterations. Butyrate is the major end product of dietary fiber bacterial fermentation in the large intestine and serves as the primary energy source for colonocytes...

Histone deacetylase 11 (HDAC11) is the only member of the class IV HDAC, and the latest member identified. It is highly expressed in brain, heart, kidney and some other organs, and located in mitochondria, cytoplasm and nuclei, depending on the tissue and cell types. Although studies in HDAC11 total knockout mice suggest its dispensable features for tissue development and life, it participates in diverse pathophysiological processes, such as DNA replication, tumor growth, immune regulation, oxidant stress injury and neurological function of cocaine...