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

The brain controls energy homeostasis and body weight by integrating various metabolic signals. Leptin, an adipose-derived hormone, conveys critical information about peripheral energy storage and availability to the brain. Leptin decreases body weight by both suppressing appetite and promoting energy expenditure. Leptin directly targets hypothalamic neurons, including AgRP and POMC neurons. These leptin-responsive neurons widely connect to other neurons in the brain, forming a sophisticated neurocircuitry that controls energy intake and expenditure. The anorexigenic actions of leptin are mediated by LEPRb, the long form of the leptin receptor, in the hypothalamus. LEPRb activates both JAK2-dependent and -independent pathways, including the STAT3, PI 3-kinase, MAPK, AMPK, and mTOR pathways. These pathways act coordinately to form a network that fully mediates leptin response. LEPRb signaling is regulated by both positive (e.g., SH2B1) and negative (e.g., SOCS3 and PTP1B) regulators and by endoplasmic reticulum stress. Leptin resistance, a primary risk factor for obesity, likely results from impairment in leptin transport, LEPRb signaling, and/or the neurocircuitry of energy balance.
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PMID:Recent advances in understanding leptin signaling and leptin resistance. 1972 19

Deficiency in the signal adaptor protein sequestosome 1 (SQSTM1/A170/p62) in mice is associated with mature-onset obesity, accompanied by insulin and leptin resistance. We previously established that redox sensitive transcription factor Nrf2 up-regulates SQSTM1 expression in response to atherogenic stimuli or laminar shear stress in vascular cells, and here examine the role of SQSTM1 in neointimal hyperplasia and vascular remodelling in vivo following carotid artery ligation. Neointimal hyperplasia was markedly enhanced at ligation sites after 3 weeks in SQSTM1(-/-) compared with wild-type (WT) mice. The intimal area and stenotic ratio were, respectively, 2.1- and 1.7-fold higher in SQSTM1(-/-) mice, indicating enhanced proliferation of vascular smooth muscle cells (SMCs). When aortic SMCs were isolated from WT and SQSTM1(-/-) mice and cultured in vitro, we found that SQSTM1(-/-) SMCs proliferated more rapidly in response to foetal calf serum (FCS) and attained 2-3-fold higher cell densities compared to WT SMCs. Moreover, migration of SQSTM1(-/-) SMCs was enhanced compared to WT SMCs. Early and late phases of p38(MAPK) activation in response to FCS stimulation were also more enhanced in SQSTM1(-/-) SMCs, and inhibitors of p38 and ERK1/2 signalling pathways significantly attenuated SMC proliferation. In summary, SQSTM1(-/-) mice exhibit enhanced neointimal hyperplasia and vascular remodelling following arterial ligation in vivo. The enhanced proliferation of SQSTM1(-/-) aortic SMCs in vitro highlights a novel role for SQSTM1 in suppressing smooth muscle proliferation following vascular injury.
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PMID:Enhanced neointimal hyperplasia and carotid artery remodelling in sequestosome 1 deficient mice. 1978 Aug 70

The uncoupling protein-1 (UCP1) is the molecular effector of thermogenesis in brown adipocytes, a process in which there is a renewed interest after the recent recognition of its relevance in adult humans. Typical white adipocytes do not express UCP1. We investigated the capacity of retinoic acid (RA), the carboxylic acid form of vitamin A and a known positive regulator of UCP1 gene transcription in brown adipocytes, to stimulate UCP1 expression in adipocytes differentiated in culture from primary mouse embryonic fibroblasts (MEFs), which are commonly used as white adipocyte model cells. Exposure to all-trans RA (ATRA), but not to rosiglitazone or isoproterenol, potently induced UCP1 expression at both the mRNA and protein level in MEF-derived adipocytes, in a dose-dependent manner. The effect on UCP1 mRNA was reproduced by retinoid receptor agonists and by retinaldehyde, required p38 mitogen-activated protein kinase activity (p38 MAPK), and appeared to be dissociated from increases in mitochondria biogenesis and oxidative capacity. MEF-derived adipocytes exhibited a high mRNA expression level of the brown fat determination factor PRDM16. The results highlight a specific potential of retinoids to induce UCP1 gene expression in adipose cells, and may have implications for the elucidation of the signaling pathways to the UCP1 gene, as well as for research using MEF-derived adipocytes.
Obesity (Silver Spring) 2010 Apr
PMID:Induction of uncoupling protein-1 in mouse embryonic fibroblast-derived adipocytes by retinoic acid. 1983 71

Oxidative myofibers, also known as slow-twitch myofibers, help maintain the metabolic health of mammals, and it has been proposed that decreased numbers correlate with increased risk of obesity. The transcriptional coactivator PPARgamma coactivator 1alpha (PGC-1alpha) plays a central role in maintaining levels of oxidative myofibers in skeletal muscle. Indeed, loss of PGC-1alpha expression has been linked to a reduction in the proportion of oxidative myofibers in the skeletal muscle of obese mice. MAPK phosphatase-1 (MKP-1) is encoded by mkp-1, a stress-responsive immediate-early gene that dephosphorylates MAPKs in the nucleus. Previously we showed that mice deficient in MKP-1 have enhanced energy expenditure and are resistant to diet-induced obesity. Here we show in mice that excess dietary fat induced MKP-1 overexpression in skeletal muscle, and that this resulted in reduced p38 MAPK-mediated phosphorylation of PGC-1alpha on sites that promoted its stability. Consistent with this, MKP-1-deficient mice expressed higher levels of PGC-1alpha in skeletal muscle than did wild-type mice and were refractory to the loss of oxidative myofibers when fed a high-fat diet. Collectively, these data demonstrate an essential role for MKP-1 as a regulator of the myofiber composition of skeletal muscle and suggest a potential role for MKP-1 in metabolic syndrome.
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PMID:MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice. 1992 Mar 56

Chronic elevation of NEFAs (non-esterified fatty acids) due to insulin resistance and obesity has been shown to be associated with increased beta-cell apoptosis and with the aetiology of the reduced beta-cell mass of Type 2 diabetes. SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase) have been implicated in the control of apoptosis. C-K [compound K; 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol] is the main intestinal bacterial metabolite of protopanaxadiol ginsenosides. Currently, little is known about the effects of C-K on beta-cells with the presence of NEFAs. The aim of the present study was to investigate the in vitro protective effect of C-K on MIN6N8 mouse insulinoma beta-cells against NEFA-induced apoptosis, as well as the modulating effect on SAPK/JNK activation. Our results have shown that C-K inhibited the palmitate-induced apoptosis through modulating SAPK/JNK activation. We conclude that C-K protects against beta-cell death and that, by anti-apoptotic activity, C-K may contribute to the previously reported anti-diabetic actions of ginseng.
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PMID:Compound K protects MIN6N8 pancreatic beta-cells against palmitate-induced apoptosis through modulating SAPK/JNK activation. 1994 45

Type 2 diabetes mellitus (T2D) is a multifactorial and genetically heterogeneous disease which leads to impaired glucose homeostasis and insulin resistance. The advanced form of disease causes acute cardiovascular, renal, neurological and microvascular complications. Thus there is a constant need to discover new and efficient treatment against the disease by seeking to uncover various novel alternate signalling mechanisms that can lead to diabetes and its associated complications. The present study allows detection of molecular targets by unravelling their role in altered biological pathways during diabetes and its associated risk factors and complications. We have used an integrated functional networks concept by merging co-expression network and interaction network to detect the transcriptionally altered pathways and regulations involved in the disease. Our analysis reports four novel significant networks which could lead to the development of diabetes and other associated dysfunctions. (a) The first network illustrates the up regulation of TGFBRII facilitating oxidative stress and causing the expression of early transcription genes via MAPK pathway leading to cardiovascular and kidney related complications. (b) The second network demonstrates novel interactions between GAPDH and inflammatory and proliferation candidate genes i.e., SUMO4 and EGFR indicating a new link between obesity and diabetes. (c) The third network portrays unique interactions PTPN1 with EGFR and CAV1 which could lead to an impaired vascular function in diabetic nephropathy condition. (d) Lastly, from our fourth network we have inferred that the interaction of beta-catenin with CDH5 and TGFBR1 through Smad molecules could contribute to endothelial dysfunction. A probability of emergence of kidney complication might be suggested in T2D condition. An experimental investigation on this aspect may further provide more decisive observation in drug target identification and better understanding of the pathophysiology of T2D and its complications.
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PMID:Expression-based network biology identifies alteration in key regulatory pathways of type 2 diabetes and associated risk/complications. 1999 58

Stearoyl-CoA Desaturase-1 (SCD1) is the rate limiting enzyme catalyzing the synthesis of monounsaturated fatty acids. Variation of SCD1 activity and the ratio of saturated to unsaturated fatty acids have been implicated in a variety of diseases including obesity, type II diabetes and cancers. In liver, many factors regulate SCD1 expression including dietary and hormonal factors such as insulin and leptin. We previously showed in hepatic cells that insulin acts through the PI3K and mTOR pathways to upregulate SCD1 expression. In the present study, using HepG2 cells, we characterized the signaling pathway mediating the leptin inhibitory response on SCD1 gene expression. We showed that leptin inhibits SCD1 at the transcriptional level. Inhibition of the ERK1/2 MAPK pathway with the PD98059 reverses the effect of leptin on SCD1 expression. Our data also demonstrated that the effect of leptin is entirely independent of the effect of insulin. Using the pharmaceutical inhibitors Ag490 and SL0101, we showed that the inhibitory effect of leptin is also mediated by the Janus Kinase 2 (Jak2) and p90RSK. EMSA and transfection experiments suggest a key role for the Sp1 transcription factor, which in turn may compete for the binding of other transcription factors such as AP-1, leading to the inhibition of SCD1 transcription. Taken together, our observations showed that, independently of insulin action, leptin exerts an inhibitory effect on SCD1 transcription via a signaling pathway implicating Jak2, ERK1/2, and p90RSK which probably targets the downstream transcription factor Sp1 on the SCD1 promoter.
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PMID:Key role of the ERK1/2 MAPK pathway in the transcriptional regulation of the Stearoyl-CoA Desaturase (SCD1) gene expression in response to leptin. 2010 24

Maternal obesity in pregnancy predisposes offspring to insulin resistance and associated cardiovascular disease. Here, we used a well-established sheep model to investigate the effects of maternal obesity on cardiac functions. Multiparous ewes were assigned to a control (CON) diet [100% of National Research Council (NRC) recommendations] or an obesogenic (OB) diet (150% of NRC recommendations) from 60 d before conception to necropsy on d 135 of pregnancy. Fetal blood glucose and insulin were increased (P<0.01, n=8) in OB (35.09+/-2.03 mg/dl and 3.40+/-1.43 microU/ml, respectively) vs. CON ewes (23.80+/-1.38 mg/dl and 0.769+/-0.256 microU/ml). Phosphorylation of AMP-activated protein kinase (AMPK), a cardioprotective signaling pathway, was reduced (P<0.05), while the stress signaling pathway, p38 MAPK, was up-regulated (P<0.05) in OB maternal and fetal hearts. Phosphorylation of c-Jun N-terminal kinase (JNK) and insulin receptor substrate-1 (IRS-1) at Ser-307 were increased (P<0.05) in OB fetal heart associated with lower downstream PI3K-Akt activity (P<0.05), indicating impaired cardiac insulin signaling. Although OB fetal hearts exhibited a normal contractile function vs. CON fetal hearts during basal perfusion, they developed an impaired heart-rate-left-ventricular-developed pressure product in response to high workload stress. Taken together, fetuses of OB mothers demonstrate alterations in cardiac PI3K-Akt, AMPK, and JNK-IRS-1 signaling pathways that would predispose them to insulin resistance and cardiac dysfunction.
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PMID:Overnutrition and maternal obesity in sheep pregnancy alter the JNK-IRS-1 signaling cascades and cardiac function in the fetal heart. 2011 Feb 68

Adipogenesis plays a key role in the pathogenesis of obesity. It begins with the commitment of mesenchymal stem cells (MSCs) to the adipocyte lineage, followed by terminal differentiation of preadipocytes to mature adipocytes. A critical, but poorly understood, component of adipogenesis involves proliferation of MSCs and preadipocytes. The present study was undertaken to examine the hypothesis that bone morphogenetic protein-3 (BMP-3) promotes adipogenesis using C3H10T1/2 MSCs and 3T3-L1 preadipocytes as in vitro model systems. We demonstrated that although it did not promote the commitment of MSCs to the adipocyte lineage or the differentiation of preadipocytes to adipocytes, BMP-3-stimulated proliferation by threefold in both cell types. Owing to a lack of information on MSC proliferation, we then delineated the molecular mechanisms underlying BMP-3-stimulated MSC proliferation. We showed that BMP-3 activated the transforming growth factor-beta (TGF-beta)/activin but not ERK1/2, p38 MAPK, or JNK signaling pathways in C3H10T1/2 cells. Furthermore, the TGF-beta/activin receptor kinase inhibitor SB-431542 blocked BMP-3-stimulated proliferation. Importantly, siRNA-mediated knockdown of the key TGF-beta/activin signaling pathway components, ActRIIB, ALK4, or Smad2, abrogated the mitogenic effects of BMP-3 on MSCs. Together, these results demonstrate that BMP-3 stimulates MSC proliferation via the TGF-beta/activin signaling pathway, thus revealing a novel role for this divergent and poorly understood member of the TGF-beta superfamily in regulating MSC proliferation.
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PMID:BMP-3 promotes mesenchymal stem cell proliferation through the TGF-beta/activin signaling pathway. 2014 30

Sarcopenia reflects a progressive withdrawal of anabolism and an increased catabolism, along with a reduced muscle regeneration capacity. Muscle force and power decline more than muscle dimensions: older muscle is intrinsically weak. Sarcopenic obesity (SO) among the elderly corroborates to the loss of muscle mass increasing the risk of metabolic syndrome development. Recent studies on the musculoskeletal adaptations with ageing and key papers on the mechanisms of muscle wasting, its functional repercussions and on SO are included. Neuropathic, hormonal, immunological, nutritional and physical activity factors contribute to sarcopenia. Selective fast fibre atrophy, loss of motor units and an increase in hybrid fibres are typical findings of ageing. Satellite cell number decreases reducing muscle regeneration capacity. SO promotes further muscle wasting and increases risk of metabolic syndrome development. The proportion of fast to slow fibres seems maintained in old age. In elderly humans, nuclear domain is maintained constant. Basal protein synthesis and breakdown show little changes in old age. Instead, blunting of the anabolic response to feeding and exercise and of the antiproteolytic effect of insulin is observed. Further understanding of the mechanisms of sarcopenia requires disentangling of the effects of ageing alone from those of disuse and disease. The causes of the greater anabolic resistance to feeding and exercise of elderly women need elucidating. The enhancement of muscle regeneration via satellite cell activation via the MAPK/notch molecular pathways seems particularly promising.
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PMID:Sarcopenia: characteristics, mechanisms and functional significance. 2020 12


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