365 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.
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
La asociación obesidad-enfermedad psiquiátrica: una necesidad más de abordaje multidisciplinar
The inhibitory effect of leptin on angiotensin II-induced vasoconstriction in vascular smooth muscle cells is mediated via a nitric oxide-dependent mechanism
Leptin inhibits the contractile response induced by angiotensin (Ang) II in vascular smooth muscle cells (VSMCs) of the aorta. We studied in vitro and ex vivo the role of nitric oxide (NO) in the effect of leptin on the Ang II-induced vasoconstriction of the aorta of 10-wk-old Wistar rats. NO and nitric oxide synthase (NOS) activity were assessed by the Griess and (3)H-arginine/citrulline conversion assays, respectively. Stimulation of inducible NOS (iNOS) as well as Janus kinases/signal transducers and activators of transcription (JAK/STAT) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were determined by Western blot. The contractile responses to Ang II were evaluated in endothelium-denuded aortic rings using the organ bath system. Changes in intracellular Ca(2+) were measured in VSMCs using fura-2 fluorescence. Leptin significantly (P < or = 0.01) stimulated NO release and NOS activity in VSMCs. Leptin's effect on NO was abolished by the NOS inhibitor, N(G)-monomethyl l-arginine, or the iNOS selective inhibitor L-N(6)-(1-iminoethyl)-lysine. Accordingly, leptin increased iNOS protein expression, with a comparable time course with that of NO production and NOS activity. Leptin also significantly increased STAT3 (P < or = 0.01) and Akt (P < or = 0.001) phosphorylation. Moreover, either the JAK2 inhibitor, AG490, or the PI3K inhibitor, wortmannin, significantly (P < or = 0.05) abrogated the leptin-induced increase in iNOS protein. Finally, both N(G)-monomethyl L-arginine and L-N(6)-(1-iminoethyl)-lysine inhibitors completely blunted (P < or = 0.001) the leptin-mediated inhibition of the Ang II-induced VSMC activation and vasoconstriction. These findings suggest that the endothelium-independent depressor action of leptin is mediated by an increase of NO bioavailability in VSMCs. This process requires the up-regulation of iNOS through mechanisms involving JAK2/STAT3 and PI3K/Akt pathways
Adipose tissue as an endocrine organ: role of leptin and adiponectin in the pathogenesis of cardiovascular diseases
Obesity, the most common nutritional disorder in industrial countries, is associated with increased cardiovascular mortality and morbidity. Nevertheless, the molecular basis linking obesity with cardiovascular disturbances have not yet been fully clarified. Recent advances in the biology of adipose tissue indicate that it is not simply an energy storage organ, but also a secretory organ, producing a variety of bioactive substances, including leptin and adiponectin, that may influence the function as well as the structural integrity of the cardiovascular system. Leptin, besides being a satiety signal for the central nervous system and to be related to insulin and glucose metabolism, may also play an important role in regulating vascular tone because of the widespread distribution of functional receptors in the vascular cells. On the other hand, the more recently discovered protein, adiponectin, seems to play a protective role in experimental models of vascular injury, in probable relation to its ability to suppress the attachment of monocytes to endothelial cells, which is an early event in the atherosclerotic process. There is already considerable evidence linking altered production of some adipocyte hormones with the cardiovascular complications of obesity. Therefore, the knowledge of alterations in the endocrine function of adipose tissue may help to further understand the high cardiovascular risk associated with obesity
Obesity as an adipose tissue dysfunction disease and a risk factor for infections – Covid-19 as a case study
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV2) disease (COVID-19) is a novel threat that hampers life expectancy especially in obese individuals. Though this association is clinically relevant, the underlying mechanisms are not fully elucidated. SARS CoV2 enters host cells via the Angiotensin Converting Enzyme 2 receptor, that is also expressed in adipose tissue. Moreover, adipose tissue is also a source of many proinflammatory mediators and adipokines that might enhance the characteristic COVID-19 cytokine storm due to a chronic low-grade inflammatory preconditioning. Further obesity-dependent thoracic mechanical constraints may also incise negatively into the prognosis of obese subjects with COVID-19. This review summarizes the current body of knowledge on the obesity-dependent circumstances triggering an increased risk for COVID-19 severity, and their clinical relevanc
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