458 research outputs found
Intracellular signalling pathways activated by leptin
Leptin is a versatile 16 kDa peptide hormone, with a tertiary
structure resembling that of members of the long-chain helical
cytokine family. It ismainly produced by adipocytes in proportion
to fat size stores, and was originally thought to act only as a
satiety factor.However, the ubiquitous distribution ofOB-R leptin
receptors in almost all tissues underlies the pleiotropism of
leptin.OB-Rs belong to the class I cytokine receptor family,which
is known to act through JAKs (Janus kinases) and STATs (signal
transducers and activators of transcription). The OB-R gene is
alternatively spliced to produce at least five isoforms. The fulllength
isoform, OB-Rb, contains intracellular motifs required for
activation of the JAK/STAT signal transduction pathway, and is
considered to be the functional receptor. Considerable evidence
for systemic effects of leptin on body mass control, reproduction,
angiogenesis, immunity, wound healing, bone remodelling and
cardiovascular function, as well as on specific metabolic pathways,
indicates that leptin operates both directly and indirectly
to orchestrate complex pathophysiological processes. Consistent
with leptin’s pleiotropic role, its participation in and crosstalk
with some of the main signalling pathways, including those
involving insulin receptor substrates, phosphoinositide 3-kinase,
protein kinase B, protein kinase C, extracellular-signal-regulated
kinase, mitogen-activated protein kinases, phosphodiesterase,
phospholipase C and nitric oxide, has been observed. The impact
of leptin on several equally relevant signalling pathways extends
also to Rho family GTPases in relation to the actin cytoskeleton,
production of reactive oxygen species, stimulation of prostaglandins,
binding to diacylglycerol kinase and catecholamine
secretion, among others
Pivotal role of nitric oxide in the control of blood pressure after leptin administration
Leptin administration has been shown to increase renal, adrenal, and lumbar
sympathetic nerve activity. However, this generalized sympathoexcitatory activity
is not always followed by an increase in arterial pressure. The present study
tested the hypothesis that leptin induces a release of nitric oxide (NO) that
opposes the pressor effect of sympathoexcitation. The effect of intravenous
administration of leptin (10, 100, and 1,000 microg/kg body wt) or vehicle on
blood pressure (BP), heart rate (HR), and serum nitrite/nitrate concentrations of
anesthetized Wistar rats was examined. At 90 min after injection, the three
leptin doses tested increased serum NO concentrations 20.5, 33.1, and 89.5%,
respectively (P < 0.001 vs. baseline). The effect of leptin on NO concentrations
was significantly dose-dependent on linear trend testing (P = 0.0001). In
contrast, leptin did not change serum nitrite/nitrate concentrations of fa/fa
rats. Leptin administration to Wistar rats under NO synthesis inhibition
(N(omega)-nitro-L-arginine methyl ester [L-NAME]) produced a statistically
significant increase (P < 0.05) in both systolic BP and mean arterial pressure as
well as in HR (P < 0.01). Injection of leptin into rats with pharmacologically
induced ganglionic blockade (chlorisondamine) was followed by a decrease in BP
and HR to values significantly lower (P < 0.01) than those observed with
chlorisondamine treatment alone. The leptin-induced hypotension observed in the
setting of ganglionic blockade was blocked by L-NAME. These findings raise the
possibility that the leptin-induced release of NO may contribute to the
homeostasis of BP
Phenotyping the obesities: reality or utopia?
In this thematic issue on phenotyping the obesities, prominent international experts offer an insightful and comprehensive collection of articles covering the current knowledge in the field. In order to actually capture all the polyhedral determinants of the diverse types of obesity, the granularity of the phenotypic information acquired must be expanded in the context of a personalized approach. Whilst the use of precision medicine has been successfully implemented in areas like cancer and other diseases, health care providers are more reluctant to embrace detailed phenotyping to guide diagnosis, treatment and prevention in obesity. Given its multiple complex layers, phenotyping necessarily needs to go beyond the multi-omics approach and incorporate all the diverse spheres that conform the reality of people living with obesity. Potential barriers, difficulties, roadblocks and opportunities together with their interaction in a syndemic context are analyzed. Plausible lacunae are also highlighted in addition to pointing to the need of redefining new conceptual frameworks. Therefore, this extraordinary collection of state-ofthe-art reviews provides useful information to both experienced clinicians and trainees as well as academics to steer clinical practice and research in the management of people living with obesity irrespective of practice setting or career stage
Childhood obesity: time for action, not complacency
The delivery of programmes through primary care has received little formal assessment, and its potential role seems to be undervalued and underused.12 Frequent contact with health professionals from an early age has been identified as an important strategy for effective management of obese children through the provision of advice, encouragement, and support for adopting healthy household eating and exercise patterns at an early stage in life.
NLRP3 Inflammasome: A Possible Link Between Obesity-Associated Low-Grade Chronic Inflammation and Colorectal Cancer Development
Emerging evidence reveals that adipose tissue-associated inflammation is a main mechanism whereby obesity promotes colorectal cancer risk and progression. Increased inflammasome activity in adipose tissue has been proposed as an important mediator of obesity-induced inflammation and insulin resistance development. Chronic inflammation in tumor microenvironments has a great impact on tumor development and immunity, representing a key factor in the response to therapy. In this context, the inflammasomes, main components of the innate immune system, play an important role in cancer development showing tumor promoting or tumor suppressive actions depending on the type of tumor, the specific inflammasome involved, and the downstream effector molecules. The inflammasomes are large multiprotein complexes with the capacity to regulate the activation of caspase-1. In turn, caspase-1 enhances the proteolytic cleavage and the secretion of the inflammatory cytokines interleukin (IL)-1β and IL-18, leading to infiltration of more immune cells and resulting in the generation and maintenance of an inflammatory microenvironment surrounding cancer cells. The inflammasomes also regulate pyroptosis, a rapid and inflammation-associated form of cell death. Recent studies indicate that the inflammasomes can be activated by fatty acids and high glucose levels linking metabolic danger signals to the activation of inflammation and cancer development. These data suggest that activation of the inflammasomes may represent a crucial step in the obesity-associated cancer development. This review will also focus on the potential of inflammasome-activated pathways to develop new therapeutic strategies for the prevention and treatment of obesity-associated colorectal cancer development
Synergistic and Detrimental Effects of Alcohol Intake on Progression of Liver Steatosis
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most
common liver disorders worldwide and the major causes of non-viral liver cirrhosis in the general
population. In NAFLD, metabolic abnormalities, obesity, and metabolic syndrome are the driving
factors for liver damage with no or minimal alcohol consumption. ALD refers to liver damage caused
by excess alcohol intake in individuals drinking more than 5 to 10 daily units for years. Although
NAFLD and ALD are nosologically considered two distinct entities, they show a continuum and
exert synergistic effects on the progression toward liver cirrhosis. The current view is that low alcohol
use might also increase the risk of advanced clinical liver disease in NAFLD, whereas metabolic
factors increase the risk of cirrhosis among alcohol risk drinkers. Therefore, special interest is now
addressed to individuals with metabolic abnormalities who consume small amounts of alcohol or
who binge drink, for the role of light-to-moderate alcohol use in fibrosis progression and clinical
severity of the liver disease. Evidence shows that in the presence of NAFLD, there is no liver-safe
limit of alcohol intake. We discuss the epidemiological and clinical features of NAFLD/ALD, aspects
of alcohol metabolism, and mechanisms of damage concerning steatosis, fibrosis, cumulative effects,
and deleterious consequences which include hepatocellular carcinoma
Leptin Inhibits the Proliferation of Vascular Smooth Muscle Cells Induced by Angiotensin II through Nitric Oxide-Dependent Mechanisms
Objective. This study was designed to investigate whether leptin modifies angiotensin (Ang) II-induced proliferation of aortic vascular smooth muscle cells (VSMCs) from 10-week-old male Wistar and spontaneously hypertensive rats (SHR), and the possible role of nitric oxide (NO). Methods. NO and NO synthase (NOS) activity were assessed by the Griess and 3H-arginine/citrulline conversion assays, respectively. Inducible NOS (iNOS) and NADPH oxidase subutnit Nox2 expression was determined by Western-blot. The proliferative responses to Ang II were evaluated through enzymatic methods. Results. Leptin inhibited the Ang II-induced proliferative response of VSMCs from control rats. This inhibitory effect of leptin was abolished by NOS inhibitor, NMMA, and iNOS selective inhibitor, L-NIL, and was not observed in leptin receptor-deficient fa/fa rats. SHR showed increased serum leptin concentrations and lipid peroxidation. Despite a similar leptin-induced iNOS up-regulation, VSMCs from SHR showed an impaired NOS activity and NO production induced by leptin, and an increased basal Nox2 expression. The inhibitory effect of leptin on Ang II-induced VSMC proliferation was attenuated. Conclusion. Leptin blocks the proliferative response to Ang II through NO-dependent mechanisms. The attenuation of this inhibitory effect of leptin in spontaneous hypertension appears to be due to a reduced NO bioavailability in VSMCs
Rapid in vivo PGC-1 mRNA upregulation in brown adipose tissue of Wistar rats by a beta(3)-adrenergic agonist and lack of effect of leptin.
Peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) is highly expressed in brown adipose tissue (BAT) and plays an important role in adaptive thermogenesis. The aim of this study was to assess the acute effect of a β3-adrenergic agonist (Trecadrine) and leptin on the expression of PGC-1 and PPARγ2 mRNA in BAT. Trecadrine produced a marked increase (4.5-fold) in PGC-1 mRNA compared to controls (P<0.001) without changes in PPARγ2 mRNA, whereas leptin administration did not alter either PGC-1 or PPARγ2 expression. These results show that selective stimulation of the β3-adrenoceptor rapidly upregulates the expression of PGC-1 in brown adipocytes without a concomitant increase in PPARγ2. Moreover, our results show that PGC-1 and PPARγ2 expression in BAT seems not to be acutely regulated by leptin
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