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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypothalamus is a specialised area in the brain that integrates the control of energy homeostasis, regulating both food intake and energy expenditure. The classical theory for hypothalamic feeding control is mainly based on the relationship between peripheral signals and neurotransmitters/neuromodulators in the central nervous system. Thus, hypothalamic neurons respond to peripheral signals, such as hormones and nutrients, by modifying the synthesis of neuropeptides. Despite the well-established role of these hypothalamic networks, increasing evidence indicates that the modulation of lipid metabolism in the hypothalamus plays a critical role in feeding control. In fact, the pharmacologic and genetic targeting of key enzymes from these pathways, such as AMP-activated protein kinase, acetyl-CoA carboxylase, carnitine palmitoyltransferase 1, fatty acid synthase, and malonyl-CoA decarboxylase, has a profound effect on food intake and body weight. Here, we review what is currently known about the relationship between hypothalamic lipid metabolism and whole body energy homeostasis. Defining these novel mechanisms may offer new therapeutic targets for the treatment of obesity and its associated pathologies.
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PMID:Hypothalamic lipids and the regulation of energy homeostasis. 2005 16

The primary objective of this study was to investigate the impact of lipid oversupply on the AMPK pathway in skeletal muscle, liver, and adipose tissue. Male Wistar rats were infused with lipid emulsion (LE) or phosphate-buffered saline for 5 h/day for 6 days. Muscles exposed to LE for 6 days exhibited increased AMPK and acetyl-CoA carboxylase (ACC) phosphorylation, along with a greater association between AMPK and Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK). No differences in muscle protein phosphatase 2C (PP2C) activity, LKB1 phosphorylation or AMPK and LKB1 association were observed. Muscle ACCbeta, and adiponectin receptor 1 (AdipoR1) mRNA levels and PPARgamma-co-activator 1alpha (PGC1alpha) protein levels were also increased in LE-treated rats. In contrast, AMPK and ACC phosphorylation decreased and PP2C activity increased in rat livers exposed to LE. Hepatic mRNA levels of ACCalpha, PPARalpha, AdipoR1, AdipoR2, and sterol regulatory element-binding protein-1c (SREBP1c) were also reduced after LE infusion. In adipose tissue, there was no significant alteration in AMPK or ACC phosphorylation. These results demonstrate that following lipid oversupply the AMPK pathway was enhanced in rat skeletal muscle while diminished in the liver and was unchanged in adipose tissue. CaMKK in skeletal muscle and PP2C in the liver, at least in part, appear to mediate these alterations. Alterations in AMPK pathway in the liver induced metabolic defects associated with lipid oversupply.
Obesity (Silver Spring) 2010 Jun
PMID:Infusion of a lipid emulsion modulates AMPK and related proteins in rat liver, muscle, and adipose tissues. 2005 67

Although germ-line deletion of c-Jun NH(2)-terminal kinase (JNK) improves overall insulin sensitivity in mice, those studies could not reveal the underlying molecular mechanism and the tissue site(s) in which reduced JNK activity elicits the observed phenotype. Given its importance in nonesterified fatty acids (NEFA) and glucose utilization, we hypothesized that the insulin-sensitive phenotype associated with Jnk deletion originates from loss of JNK function in skeletal muscle. Short hairpin RNA (shRNA)-mediated gene silencing was used to identify the functions of JNK subtypes in regulating energy metabolism and metabolic responses to elevated concentrations of NEFA in C2C12 myotubes, a cellular model of skeletal muscle. We show for the first time that cellular JNK2- and JNK1/JNK2-deficiency divert glucose from oxidation to glycogenesis due to increased glycogen synthase (GS) activity and induction of Pdk4. We further show that JNK2- and JNK1/JNK2-deficiency profoundly increase cellular NEFA oxidation, and their conversion to phospholipids and triglyceride. The increased NEFA utilization was coupled to increased expressions of selective NEFA handling genes including Cd36, Acsl4, and Chka, and enhanced palmitic acid (PA)-dependent suppression of acetyl-CoA carboxylase (Acc). In JNK-intact cells, PA inhibited insulin signaling and glycogenesis. Although silencing Jnk1 and/or Jnk2 prevented PA-induced inhibition of insulin signaling, it did not completely block decreased insulin-mediated glycogenesis, thus indicating JNK-independent pathways in the suppression of glycogenesis by PA. Muscle-specific inhibition of JNK2 (or total JNK) improves the capacity of NEFA utilization and glycogenesis, and is a potential therapeutic target for improving systemic insulin sensitivity in type 2 diabetes (T2D).
Obesity (Silver Spring) 2010 Sep
PMID:JNK deficiency enhances fatty acid utilization and diverts glucose from oxidation to glycogen storage in cultured myotubes. 2009 41

Artemisia sacrorum Ledeb. (Compositae) (ASL) is a traditional Chinese medicine used to treat different hepatic diseases. However, a hypolipidemic effect of ASL on fatty liver disease has not been reported. Therefore, we investigated whether 95% ethanol eluate (EE), an active part of ASL, would attenuate hepatic lipid accumulation in human HepG2 cells by activating AMP-activated protein kinase (AMPK). Significant decreases in triglyceride levels and increases in AMPK and acetyl-CoA carboxylase (ACC) phosphorylation were observed when the cells were treated with 95% EE. EE down-regulated the lipogenesis gene expression of sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1), in a time- and dose-dependent manner. In contrast, the lipolytic gene expression of peroxisome proliferator-activated receptor alpha (PPAR-alpha) and CD36 increased in a time- and dose-dependent manner. These effects were abolished by pretreatment with compound C, an AMPK inhibitor. However, there were no differences in the gene expression of SREBP2, low density lipoprotein receptor (LDLR), hydroxymethyl glutaryl CoA reductase (HMG-CoA), or glucose transporter 2 (GLUT2). At the same time, 95% EE significantly increased the gene expression of acyl CoA oxidase (ACOX) in a time- and dose-dependent manner. Thus, AMPK mediated 95% EE induced suppression of SREBP1c and activation of PPAR-alpha respectively. These finding indicate that 95% EE attenuates hepatic lipid accumulation through AMPK activation and may be active in the prevention of serious diseases such as fatty liver, obesity, and type-2 diabetic mellitus.
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PMID:An active part of Artemisia sacrorum Ledeb. attenuates hepatic lipid accumulation through activating AMP-activated protein kinase in human HepG2 cells. 2013 13

Both glucocorticoid and insulin are known to have an anabolic effect on lipogenesis. Acetyl-CoA, an intermediate product of glycolysis, is supplied for fatty acid synthesis when carbohydrate intake is sufficient. Acetyl-CoA carboxylase (ACC), consisting of two isoenzymes ACC1 and ACC2, mediates the conversion from acetyl-CoA to malonyl-CoA, and thus plays a key role for the regulation of lipogenesis. In this study, we surveyed the effects of glucocorticoid and insulin on the transcriptional activity of the alternative promoters of ACCs (PI-PIII for ACC1, and PI and PII for ACC2) using the HepG2 human hepatocyte cell line in vitro. We also examined the roles of the insulin and/or glucose-regulated transcriptional factor(s) such as SREBP1c, LXRalpha/beta, and ChREBP on each promoter of the ACC genes. We found that both insulin and glucocorticoid had potent positive effects on all the promoters examined, and additive effects of both hormones were recognized in ACC1 PI and ACC2 PI. Furthermore, a representative insulin-responsive transcription factor SREBP1c showed significant stimulatory effects on all the promoters of ACC genes, among which those on ACC1 PIII and ACC2 PI were most prominent. On the other hand, the effect of LXRalpha was rather selective; it showed a marked stimulatory effect only on ACC1 PII. LXRbeta and ChREBP had minimal, if any, effects on some of the promoters. Altogether, our data suggest that insulin and glucocorticoid have positive effects on both ACC1 and ACC2 gene transcription. SREBP1c might be a master regulator of the expression of both genes regardless of the promoter utilized, whereas LXRalpha seems to play a promoter-specific role. Since ACC1 facilitates lipogenesis by stimulating fatty acid synthesis and ACC2 inhibits lipolysis, both insulin and glucocorticoid seem to play an important role in the pathogenesis of obesity and/or hepatic steatosis.
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PMID:Hormonal regulation of acetyl-CoA carboxylase isoenzyme gene transcription. 2013 35

Deposition and mobilization of fat in an organism are tightly controlled by multiple levels of endocrine and neuroendocrine regulation. Because these hormonal mechanisms ultimately act by affecting biochemical reactions of fat synthesis or utilization, obesity could be also modulated by altering directly the underlying lipid biochemistry. We have previously shown that genetically modified mice with an elevated level of the lipid peroxidation product 4-HNE become obese. We now demonstrate that the process is phylogenetically conserved and thus likely to be universal. In the nematode C. elegans, disruption of either conjugation or oxidation of 4-HNE leads to fat accumulation, whereas augmentation of 4-HNE conjugation results in a lean phenotype. Moreover, direct treatment of C. elegans with synthetic 4-HNE causes increased lipid storage, directly demonstrating a causative role of 4-HNE. The postulated mechanism, which involves modulation of acetyl-CoA carboxylase activity, could contribute to the triggering and maintenance of the obese phenotype on a purely metabolic level.
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PMID:Fat accumulation in Caenorhabditis elegans triggered by the electrophilic lipid peroxidation product 4-hydroxynonenal (4-HNE). 2015 89

Emerging evidence suggests that cannabinoids play an important role in the modulation of fatty liver, which appears to be mediated via activation of cannabinoid receptors. Steatogenic agents such as ethanol and high-fat diet can upregulate the activity of cannabinoid 1 (CB1) receptors via increasing synthesis of endocannabinoids, 2-arachidonoylglycerol, and anandamide. CB1 receptors can also be upregulated by obesity. CB1 receptor activation results in upregulation of lipogenic transcription factor, sterol regulatory element-binding protein 1c and its target enzymes, acetyl-CoA carboxylase-1, and fatty acid synthase and concomitantly, downregulation of carnitine palmitoyltransferase-1. This leads to increased de novo fatty acid synthesis as well as decreased fatty acid oxidation, culminating into the development of fatty liver. High-fat diet, in addition to CB1 receptor activation, appears to activate CB2 receptors that may also contribute to fatty liver. In non-alcoholic fatty liver disease, CB2 receptor activation is associated with the development of fatty liver. Cannabis smoking can increase the severity of fatty liver in hepatitis C patients although the precise mechanism is unknown. As the mechanisms involved in endocannabinoid receptor signaling are being increasingly well understood and the biosynthetic regulatory elements elucidated, these present good opportunity for the pharmaceutical scientists to design drugs to treat liver diseases, including steatosis, based on the cannabinoids, endocannabinoids, and related templates.
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PMID:Role of cannabinoids in the development of fatty liver (steatosis). 2020 61

De novo lipogenesis (DNL) is a complex yet highly regulated metabolic pathway, and transcription factors such as liver X receptor (LXR), sterol regulatory element-binding protein-1c (SREBP-1c), and carbohydrate response element binding protein (ChREBP) exert significant control over the de novo synthesis of fatty acids. An increase in de novo lipogenesis (DNL) is an important contributor to increased fat mass, while a reduction in lipogenesis may be protective against the development of obesity. In this review, we explore fatty acid synthesis in the context of new insights gleaned from global and tissue-specific gene knockout mouse models of enzymes involved in fatty acid synthesis, namely acetyl-CoA carboxylase, fatty acid synthase, fatty acid elongase 6, and stearoyl-CoA desaturase 1. A disruption in fatty acid synthesis, induced by the deficiency of any one of these enzymes, affects lipid metabolism and in some cases may protect against obesity in a tissue and gene-specific manner, as discussed in detail in this review.
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PMID:Genetic control of de novo lipogenesis: role in diet-induced obesity. 2021 65

The molecular mechanisms responsible for the association of obesity with adverse colon cancer outcomes are poorly understood. We investigated the effects of a high-energy diet on growth of an in vivo colon cancer model. Seventeen days following the injection of 5x10(5) MC38 colon carcinoma cells, tumors from mice on the high-energy diet were approximately twice the volume of those of mice on the control diet. These findings were correlated with the observation that the high-energy diet led to elevated insulin levels, phosphorylated AKT, and increased expression of fatty acid synthase (FASN) by the tumor cells. Metformin, an antidiabetic drug, leads to the activation of AMPK and is currently under investigation for its antineoplastic activity. We observed that metformin blocked the effect of the high-energy diet on tumor growth, reduced insulin levels, and attenuated the effect of diet on phosphorylation of AKT and expression of FASN. Furthermore, the administration of metformin led to the activation of AMPK, the inhibitory phosphorylation of acetyl-CoA carboxylase, the upregulation of BNIP3 and increased apoptosis as estimated by poly (ADP-ribose) polymerase (PARP) cleavage. Prior work showed that activating mutations of PI3K are associated with increased AKT activation and adverse outcome in colon cancer; our results demonstrate that the aggressive tumor behavior associated with a high-energy diet has similar effects on this signaling pathway. Furthermore, metformin is demonstrated to reverse the effects of the high-energy diet, thus suggesting a potential role for this agent in the management of a metabolically defined subset of colon cancers.
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PMID:Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. 2022 37

Inhibition of acetyl-CoA carboxylase (ACC) is one approach used for treating metabolic syndrome. Using partially purified ACC to screen herbs commonly used in Taiwanese folk medicine, we previously showed that an ethanol extract of Polygonum hypoleucum Ohwi (EP) had potent ACC inhibitory activity and partially alleviated metabolic disorders induced by a high fat diet. Since ACC plays a crucial role in de novo lipogenesis, the favorable effects of EP on metabolism were tested under lipogenic conditions in the present study. On incubating high glucose (30 mM)-stimulated HepG2 cells with EP (72.5 or 145 microg/mL), ACC and fatty acid synthase activity, triacylglycerol content, and microsomal triacylglycerol transfer protein mRNA levels were all significantly reduced (P < 0.05, vs vehicle). When EP was given at low, medium, and high dosages (94, 188, and 470 mg/kg) to sucrose water-treated Wistar rats for four weeks, alleviation of symptoms associated with metabolic syndrome, including obesity, insulin resistance, hypertriglyceridemia, and hypertension, accompanied by hepatic ACC inactivation, was seen in the low dosage group. Four compounds (emodin, emodin-8-O-beta-D-glucopyranoside, (+)-catechin, and (-)-epicatechin) isolated from EP were identified as ACC inhibitors. These results confirm that P. hypoleucum Ohwi, acting partly through ACC inhibition, has favorable effects in alleviating metabolic disturbances occurring under lipogenic conditions.
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PMID:The metabolic benefits of Polygonum hypoleucum Ohwi in HepG2 cells and Wistar rats under lipogenic stress. 2023 58


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