RÉSUMÉ
In parallel to the legalization of cannabis for both medicinal and recreational purposes, cannabinoid use has steadily increased over the last decade in the United States. Cannabinoids, such as tetrahydrocannabinol and anandamide, bind to the central cannabinoid-1 (CB1) receptor to impact several physiological processes relevant for body weight regulation, including appetite and energy expenditure. The hypothalamus integrates peripheral signals related to energy balance, houses several nuclei that orchestrate eating, and expresses the CB1 receptor. Herein we review literature to date concerning cannabinergic action in the hypothalamus with a specific focus on eating behaviors. We highlight hypothalamic areas wherein researchers have focused their attention, including the lateral, arcuate, paraventricular, and ventromedial hypothalamic nuclei, and interactions with the hormone leptin. This review serves as a comprehensive analysis of what is known about cannabinoid signaling in the hypothalamus, highlights gaps in the literature, and suggests future directions.
Sujet(s)
Cannabinoïdes , Comportement alimentaire , Hypothalamus , Récepteur cannabinoïde de type CB1 , Transduction du signal , Humains , Animaux , Hypothalamus/métabolisme , Comportement alimentaire/physiologie , Récepteur cannabinoïde de type CB1/métabolisme , Leptine/métabolisme , Métabolisme énergétiqueRÉSUMÉ
Decidualisation of the endometrium is a key event in early pregnancy, which enables embryo implantation. Importantly, the molecular processes impairing decidualisation in obese mothers are yet to be characterised. We hypothesise that impaired decidualisation in obese mice is mediated by the upregulation of leptin modulators, the suppressor of cytokine signalling 3 (SOCS3) and the protein tyrosine phosphatase non-receptor type 2 (PTPN2), together with the disruption of progesterone (P4)-signal transducer and activator of transcription (STAT3) signalling. After feeding mice with chow diet (CD) or high-fat diet (HFD) for 16 weeks, we confirmed the downregulation of P4 and oestradiol (E2) steroid receptors in decidua from embryonic day (E) 6.5 and decreased proliferation of stromal cells from HFD. In vitro decidualised mouse endometrial stromal cells (MESCs) and E6.5 deciduas from the HFD showed decreased expression of decidualisation markers, followed by the upregulation of SOCS3 and PTPN2 and decreased phosphorylation of STAT3. In vivo and in vitro leptin treatment of mice and MESCs mimicked the results observed in the obese model. The downregulation of Socs3 and Ptpn2 after siRNA transfection of MESCs from HFD mice restored the expression level of decidualisation markers. Finally, DIO mice placentas from E18.5 showed decreased labyrinth development and vascularisation and fetal growth restricted embryos. The present study revealed major defects in decidualisation in obese mice, characterised by altered uterine response to E2 and P4 steroid signalling. Importantly, altered hormonal response was associated with increased expression of leptin signalling modulators SOCS3 and PTPN2. Elevated levels of SOCS3 and PTPN2 were shown to molecularly affect decidualisation in obese mice, potentially disrupting the STAT3-PR regulatory molecular hub.
Sujet(s)
Caduques , Retard de croissance intra-utérin , Leptine , Placenta , Transduction du signal , Animaux , Femelle , Souris , Grossesse , Caduques/métabolisme , Caduques/anatomopathologie , Alimentation riche en graisse/effets indésirables , Retard de croissance intra-utérin/métabolisme , Retard de croissance intra-utérin/anatomopathologie , Leptine/métabolisme , Souris de lignée C57BL , Souris obèse , Obésité/métabolisme , Obésité/anatomopathologie , Placenta/métabolisme , Progestérone/métabolisme , Protein Tyrosine Phosphatase, Non-Receptor Type 2/métabolisme , Protein Tyrosine Phosphatase, Non-Receptor Type 2/génétique , Facteur de transcription STAT-3/métabolisme , Cellules stromales/métabolisme , Protéine-3 suppressive de la signalisation des cytokine/métabolisme , Protéine-3 suppressive de la signalisation des cytokine/génétiqueRÉSUMÉ
The hormone leptin is critical for regulation of food intake, energy expenditure and overall metabolism. However, the mechanisms that promote leptin secretion from adipocytes in response to nutrient surplus and limit its secretion during nutrient scarcity are unclear. New work reveals that the autophagy protein Atg8/LC3 has a bidirectional role in leptin secretion, both facilitating and limiting its release.
Sujet(s)
Autophagie , Leptine , Autophagie/physiologie , Animaux , Leptine/métabolisme , Nutriments/métabolisme , Adipocytes/métabolisme , Humains , Protéines associées aux microtubules/métabolisme , Protéines associées aux microtubules/génétique , Métabolisme énergétique , Famille de la protéine-8 associée à l'autophagie/métabolisme , Famille de la protéine-8 associée à l'autophagie/génétiqueRÉSUMÉ
Nonalcoholic fatty liver disease (NAFLD) affects over a third of the US population and 25% globally, with current treatments proving ineffective. This study investigates whether manipulating brown adipose tissue (BAT) and beige fat activity by housing C57BL/6J mice at thermoneutral (27 °C) or standard temperatures (22 °C) impacts NAFLD development. Male mice were fed either a chow diet (CHD) or a "fast food" diet (FFD) for 10 weeks. Mice at 27 °C had reduced food intake but increased body weight and plasma leptin levels. FFD-fed mice at 27 °C had greater liver weight (2.6 vs. 1.8 g), triglyceride content (7.6 vs. 3.9 mg/g), and hepatic steatosis compared to those at 22 °C. Gene expression of fatty acid synthase, sterol regulatory element-binding protein 1, and fatty acid translocase CD36 was elevated in FFD-fed mice at 27 °C, but not in CHD-fed mice. Thermoneutral housing also reduced expression of thermogenic markers in BAT and inguinal white adipose tissue (WAT) and caused BAT whitening. In conclusion, thermoneutrality inhibits thermogenic markers and exacerbates NAFLD. Activating BAT or promoting WAT browning via cold exposure or other stimuli may offer a strategy for managing NAFLD.
Sujet(s)
Tissu adipeux brun , Souris de lignée C57BL , Stéatose hépatique non alcoolique , Thermogenèse , Animaux , Stéatose hépatique non alcoolique/métabolisme , Stéatose hépatique non alcoolique/étiologie , Souris , Tissu adipeux brun/métabolisme , Mâle , Tissu adipeux blanc/métabolisme , Foie/métabolisme , Foie/anatomopathologie , Marqueurs biologiques , Modèles animaux de maladie humaine , Poids , Leptine/sang , Leptine/métabolisme , Triglycéride/sang , Triglycéride/métabolismeRÉSUMÉ
Syrian hamsters are valuable models for studying lipid metabolism due to their sensitivity to dietary cholesterol, yet the precise impact of varying cholesterol levels has not been comprehensively assessed. This study examined the impact of varying dietary cholesterol levels on lipid metabolism in Syrian hamsters. Diets ranging from 0% to 1% cholesterol were administered to assess lipid profiles and oxidative stress markers. Key findings indicate specific cholesterol thresholds for inducing distinct lipid profiles: below 0.13% for normal lipids, 0.97% for elevated LDL-C, 0.43% for increased VLDL-C, and above 0.85% for heightened hepatic lipid accumulation. A cholesterol supplementation of 0.43% induced hypercholesterolemia without adverse liver effects or abnormal lipoprotein expression. Furthermore, cholesterol supplementation significantly increased liver weight, plasma total cholesterol, LDL-C, and VLDL-C levels while reducing the HDL-C/LDL-C ratio. Fecal cholesterol excretion increased, with stable bile acid levels. High cholesterol diets correlated with elevated plasma ALT activities, reduced hepatic lipid peroxidation, and altered leptin and CETP levels. These findings underscore Syrian hamsters as robust models for hyperlipidemia research, offering insights into experimental methodologies. The identified cholesterol thresholds facilitate precise lipid profile manipulation, enhancing the hamster's utility in lipid metabolism studies and potentially informing clinical approaches to managing lipid disorders.
Sujet(s)
Cholestérol alimentaire , Métabolisme lipidique , Foie , Mesocricetus , Animaux , Cholestérol alimentaire/administration et posologie , Foie/métabolisme , Mâle , Cricetinae , Fèces/composition chimique , Stress oxydatif , Hypercholestérolémie/métabolisme , Hypercholestérolémie/sang , Cholestérol LDL/sang , Peroxydation lipidique , Cholestérol/sang , Cholestérol/métabolisme , Acides et sels biliaires/métabolisme , Leptine/sang , Leptine/métabolisme , Protéines de transfert des esters de cholestérol/métabolismeRÉSUMÉ
BACKGROUND: Diabetes mellitus (DM) presents impediment to wound healing. While ultraviolet B (UVB) exposure showed therapeutic potential in various skin conditions, its capacity to mediate diabetic wound healing remains unclear. To investigate the efficacy of UVB on wound healing and its underlying basis. MATERIALS AND METHODS: Male C57BL/6 mice were subjected to the high-fat diet followed by streptozotocin administration to establish the diabetic model. Upon confirmation of diabetes, full-thickness wounds were inflicted and the treatment group received UVB radiation at 50 mJ/cm2 for 5 min every alternate day for 2 weeks. Wound healing rate was then assessed, accompanied by evaluations of blood glucose, lipid profiles, CD31 expression, and concentrations of ghrelin and leptin. Concurrently, in vitro studies were executed to evaluate the protective role of ghrelin on human umbilical vein endothelial cells (HUVEC) under high glucose (HG) conditions. RESULTS: Post UVB exposure, there was a marked acceleration in wound healing in DM mice without alterations in hyperglycemia and lipid profiles. Compared to non-UVB-exposed mice, the UVB group showed enhanced angiogenesis manifested by a surge in CD31 expression. This trend appeared to be in harmony with the elevated ghrelin levels. In vitro experiments indicated that ghrelin significantly enhanced the migratory pace and angiogenic properties of HUVEC under HG-induced stress, potentially mediated by an upregulation in vascular endothelial growth factor expression. CONCLUSION: UVB exposure bolstered wound healing in diabetic mice, plausibly mediated through augmented angiogenesis induced by ghrelin secretion. Such findings underscore the vast potential of UVB-induced ghrelin in therapeutic strategies targeting diabetic wound healing.
Sujet(s)
Diabète expérimental , Ghréline , Cellules endothéliales de la veine ombilicale humaine , Souris de lignée C57BL , Cicatrisation de plaie , Animaux , Humains , Mâle , Souris , Glycémie/métabolisme , Ghréline/métabolisme , Ghréline/effets des radiations , Leptine/métabolisme , Antigènes CD31/métabolisme , Peau/effets des radiations , Peau/anatomopathologie , Peau/métabolisme , Rayons ultraviolets/effets indésirables , Traitement par ultraviolets/méthodes , Cicatrisation de plaie/effets des radiationsRÉSUMÉ
OBJECTIVE: To investigate the cerebroprotective effects of leptin in vitro and in vivo via the Janus kinase-2 (JAK2)/transcription factor signal transducer and activators of transcription-3 (STAT3) pathway and leptin receptors (LEPR). METHODS: The study used the cellular oxygen-glucose deprivation (OGD) model in PC12 cells and the middle cerebral artery occlusion (MCAO) rat model of cerebral ischaemia-reperfusion injury (CIRI) to assess changes in gene expression and protein levels following leptin pretreatment. The methylated DNA immunoprecipitation (MeDIP) assay measured DNA methylation levels. RESULTS: The optimal leptin concentration for exerting neuroprotective effects against ischaemia-reperfusion injury in PC12 cells was 200 ng/ml in vitro, but excessive leptin diminished this effect. Leptin pretreatment in the MCAO rat model demonstrated a similar effect to previously reported leptin administration post-CIRI. In addition to regulating the expression of inflammation-related cytokines, Western blot analysis showed that leptin pretreatment upregulated BCL-2 and downregulated caspase 3 levels. The MeDIP analysis demonstrated that DNA methylation regulated LEPR gene expression in the MCAO rat model when leptin pretreatment was used. CONCLUSION: Exogenous leptin might bind to extra-activated LEPR by reducing the methylation level of the LEPR gene promoter region, which leads to an increase in phosphorylated JAK2/STAT3 and apoptotic signalling pathways.
Sujet(s)
Méthylation de l'ADN , Kinase Janus-2 , Leptine , Rat Sprague-Dawley , Récepteurs à la leptine , Lésion d'ischémie-reperfusion , Facteur de transcription STAT-3 , Transduction du signal , Animaux , Lésion d'ischémie-reperfusion/métabolisme , Lésion d'ischémie-reperfusion/anatomopathologie , Kinase Janus-2/métabolisme , Rats , Facteur de transcription STAT-3/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Récepteurs à la leptine/métabolisme , Récepteurs à la leptine/génétique , Mâle , Leptine/métabolisme , Cellules PC12 , Infarctus du territoire de l'artère cérébrale moyenne/métabolisme , Infarctus du territoire de l'artère cérébrale moyenne/anatomopathologie , Modèles animaux de maladie humaine , Neuroprotecteurs/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Encéphalopathie ischémique/métabolisme , Encéphalopathie ischémique/anatomopathologie , Caspase-3/métabolismeRÉSUMÉ
Mammals have evolved sex-specific adaptations to reduce energy usage in times of food scarcity. These adaptations are well described for peripheral tissue, though much less is known about how the energy-expensive brain adapts to food restriction, and how such adaptations differ across the sexes. Here, we examined how food restriction impacts energy usage and function in the primary visual cortex (V1) of adult male and female mice. Molecular analysis and RNA sequencing in V1 revealed that in males, but not in females, food restriction significantly modulated canonical, energy-regulating pathways, including pathways associated waith AMP-activated protein kinase, peroxisome proliferator-activated receptor alpha, mammalian target of rapamycin, and oxidative phosphorylation. Moreover, we found that in contrast to males, food restriction in females did not significantly affect V1 ATP usage or visual coding precision (assessed by orientation selectivity). Decreased serum leptin is known to be necessary for triggering energy-saving changes in V1 during food restriction. Consistent with this, we found significantly decreased serum leptin in food-restricted males but no significant change in food-restricted females. Collectively, our findings demonstrate that cortical function and energy usage in female mice are more resilient to food restriction than in males. The neocortex, therefore, contributes to sex-specific, energy-saving adaptations in response to food restriction.
Sujet(s)
Métabolisme énergétique , Néocortex , Animaux , Femelle , Mâle , Néocortex/physiologie , Néocortex/métabolisme , Souris , Cortex visuel/physiologie , Cortex visuel/métabolisme , Facteurs sexuels , Privation alimentaire/physiologie , Souris de lignée C57BL , Caractères sexuels , Leptine/métabolisme , Leptine/sang , Adaptation physiologique , Restriction caloriqueRÉSUMÉ
Accumulation of hyper-phosphorylated tau and amyloid beta (Aß) are key pathological hallmarks of Alzheimer's disease (AD). Increasing evidence indicates that in the early pre-clinical stages of AD, phosphorylation and build-up of tau drives impairments in hippocampal excitatory synaptic function, which ultimately leads to cognitive deficits. Consequently, limiting tau-related synaptic abnormalities may have beneficial effects in AD. There is now significant evidence that the hippocampus is an important brain target for the endocrine hormone leptin and that leptin has pro-cognitive properties, as activation of synaptic leptin receptors markedly influences higher cognitive processes including learning and memory. Clinical studies have identified a link between the circulating leptin levels and the risk of AD, such that AD risk is elevated when leptin levels fall outwith the physiological range. This has fuelled interest in targeting the leptin system therapeutically. Accumulating evidence supports this possibility, as numerous studies have shown that leptin has protective effects in a variety of models of AD. Recent findings have demonstrated that leptin has beneficial effects in the preclinical stages of AD, as leptin prevents the early synaptic impairments driven by tau protein and amyloid ß. Here we review recent findings that implicate the leptin system as a potential novel therapeutic target in AD.
Sujet(s)
Maladie d'Alzheimer , Leptine , Synapses , Maladie d'Alzheimer/métabolisme , Maladie d'Alzheimer/traitement médicamenteux , Humains , Leptine/métabolisme , Animaux , Synapses/métabolisme , Peptides bêta-amyloïdes/métabolisme , Protéines tau/métabolisme , Récepteurs à la leptine/métabolisme , Hippocampe/métabolismeRÉSUMÉ
Konjac glucomannan (KGM), high-viscosity dietary fiber, is utilized in weight management. Previous investigations on the appetite-suppressing effects of KGM have centered on intestinal responses to nutrients and gastric emptying rates, with less focus on downstream hypothalamic neurons of satiety hormones. In our studies, the molecular mechanisms through which KGM and its degradation products influence energy homeostasis via the adipocyte-hypothalamic axis have been examined. It was found that high-viscosity KGM more effectively stimulates enteroendocrine cells to release glucagon-like peptide-1 (GLP-1) and reduces ghrelin production, thereby activating hypothalamic neurons and moderating short-term satiety. Conversely, low-viscosity DKGM has been shown to exhibit stronger anti-inflammatory properties in the hypothalamus, enhancing hormone sensitivity and lowering the satiety threshold. Notably, both KGM and DKGM significantly reduced leptin signaling and fatty acid signaling in adipose tissue and activated brown adipose tissue thermogenesis to suppress pro-opiomelanocortin (POMC) expression and activate agouti-related protein (AgRP) expression, thereby reducing food intake and increasing energy expenditure. Additionally, high-viscosity KGM has been found to activate the adipocyte-hypothalamus axis more effectively than DKGM, thereby promoting greater daily energy expenditure. These findings provide novel insights into the adipocyte-hypothalamic axis for KGM to suppress appetite and reduce weight.
Sujet(s)
Adipocytes , Régulation de l'appétit , Alimentation riche en graisse , Métabolisme énergétique , Hypothalamus , Souris de lignée C57BL , Animaux , Souris , Métabolisme énergétique/effets des médicaments et des substances chimiques , Hypothalamus/métabolisme , Hypothalamus/effets des médicaments et des substances chimiques , Alimentation riche en graisse/effets indésirables , Mâle , Régulation de l'appétit/effets des médicaments et des substances chimiques , Adipocytes/métabolisme , Adipocytes/effets des médicaments et des substances chimiques , Humains , Glucagon-like peptide 1/métabolisme , Ghréline/métabolisme , Leptine/métabolisme , Protéine apparentée à Agouti/métabolisme , Protéine apparentée à Agouti/génétique , Thermogenèse/effets des médicaments et des substances chimiques , Pro-opiomélanocortine/métabolisme , Pro-opiomélanocortine/génétique , Obésité/métabolisme , Obésité/physiopathologie , Obésité/diétothérapie , MannanesRÉSUMÉ
BACKGROUND: Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process. METHODS: Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4 (ANGPTL4) phosphorylation. RESULTS: We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive (N+) GC and further demonstrated that a high-fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity-related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase-2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis. CONCLUSIONS: Leptin-induced phosphorylation of ANGPTL4 facilitates LPL-mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC.
Sujet(s)
Leptine , Lipoprotein lipase , Métastase lymphatique , Tumeurs de l'estomac , Lipoprotein lipase/métabolisme , Tumeurs de l'estomac/métabolisme , Tumeurs de l'estomac/anatomopathologie , Humains , Animaux , Souris , Leptine/métabolisme , Métabolisme lipidique , Mâle , Lignée cellulaire tumorale , Protéine-4 similaire à l'angiopoïétine/métabolisme , Femelle , PhosphorylationRÉSUMÉ
BACKGROUND: A wealth of evidence underscores the bioactive properties of nutraceuticals and functional foods in addressing oxyinflammatory-based diseases with implications at both peripheral and central levels. Opuntia ficus-indica (OFI) is well-documented for its health-promoting attributes, though its fruit (OFIF) remains relatively understudied. Not only poses Metabolic Syndrome (MetS) cardiometabolic risks but also contributes significantly to cognitive impairment, especially in crucial brain areas such as hippocampus and hypothalamus. METHODS: Following 8 weeks of HFD to induce MetS, rats received OFIF oral supplementation for 4 weeks to evaluate cognitive and affective modifications using behavioural paradigms, i.e. open field, burrowing, white-dark box, novelty-suppressed feeding, and object recognition tests. Our investigation extended to biochemical evaluations of lipid homeostasis, central and peripheral oxidative stress and neurotrophic pathways, correlating these measures together with circulating leptin levels. RESULTS: Our data revealed that OFIF modulation of leptin positively correlates with systemic and brain oxidative stress, with markers of increased anxiety-like behaviour and impaired lipid homeostasis. On the other hand, leptin levels reduced by OFIF are associated with improved antioxidant barriers, declarative memory and neurotrophic signalling. DISCUSSION: This study underscores OFIF neuroactive potential in the context of MetS-associated cognitive impairment, offering insights into its mechanisms and implications for future therapeutic strategies.
Sujet(s)
Cognition , Alimentation riche en graisse , Modèles animaux de maladie humaine , Fruit , Métabolisme lipidique , Syndrome métabolique X , Opuntia , Stress oxydatif , Animaux , Stress oxydatif/effets des médicaments et des substances chimiques , Opuntia/composition chimique , Syndrome métabolique X/traitement médicamenteux , Syndrome métabolique X/métabolisme , Mâle , Cognition/effets des médicaments et des substances chimiques , Rats , Alimentation riche en graisse/effets indésirables , Métabolisme lipidique/effets des médicaments et des substances chimiques , Rat Wistar , Leptine/sang , Leptine/métabolisme , Extraits de plantes/pharmacologie , Antioxydants/pharmacologie , Comportement animal/effets des médicaments et des substances chimiques , Dysfonctionnement cognitif/métabolisme , Dysfonctionnement cognitif/traitement médicamenteuxRÉSUMÉ
This study involved 45 Holstein and 60 Holstein-Charolaise steers, tailored with specific diets according to breed and rearing systems. DNA genotyping was conducted for DGAT1, LEP, SCD1, SREBF1, and TG genes to investigate their impact on carcass conformation traits, beef quality traits, and sensory quality traits. The results showed associations between the genetic variants and the analyzed traits. Specifically, DGAT1 was found to affect drip loss, meat brightness, and color saturation. The TG gene was associated with marbling and meat color. LEP influenced trim fat and pH levels, while SCD1 was linked to metabolic energy live weight gains, and pH levels. SREBF1 was related to fatness.
Sujet(s)
Viande rouge , Animaux , Bovins/génétique , Marqueurs génétiques , Viande rouge/normes , Viande rouge/analyse , Mâle , Diacylglycerol O-acyltransferase/génétique , Viande/analyse , Acyl-(acyl-carrier-protein)desaturase/génétique , Protéine-1 de liaison à l'élément de régulation des stérols/génétique , Leptine/génétique , Leptine/métabolisme , GénotypeRÉSUMÉ
Non-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in â¼ 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours. Interestingly, two kinase inhibitors, Piceatannol and Tyrphostin 23, appeared to exert synthetic lethality with LKB1 mutations. Although LKB1 loss alone accelerates energy expenditure, unexpectedly we find that it additionally alters regulation of the key energy homeostasis maintenance player leptin (LEP), further increasing the energetic burden and exposing a vulnerable point; acquired sensitivity to the identified compounds. We show that compound treatment stabilises Hypoxia-inducible factor 1-alpha (HIF1A) by antagonising Von Hippel-Lindau (VHL)-mediated HIF1A ubiquitination, driving LEP hyperactivation. Importantly, we demonstrate that sensitivity to piceatannol/tyrphostin 23 epistatically relies on a HIF1A-LEP-Uncoupling Protein 2 (UCP2) signaling axis lowering cellular energy beyond survival, in already challenged LKB1-deficient cells. Thus, we uncover a pivotal metabolic vulnerability of LKB1-deficient tumours, which may be therapeutically exploited using our identified compounds as mitochondrial uncouplers.
Sujet(s)
AMP-activated protein kinase kinases , Leptine , Mitochondries , Protein-Serine-Threonine Kinases , Danio zébré , Humains , Animaux , Protein-Serine-Threonine Kinases/métabolisme , Protein-Serine-Threonine Kinases/génétique , Mitochondries/métabolisme , Mitochondries/effets des médicaments et des substances chimiques , Leptine/métabolisme , Tumeurs du poumon/métabolisme , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/métabolisme , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/anatomopathologie , Agents découplants/pharmacologie , Sous-unité alpha du facteur-1 induit par l'hypoxie/métabolisme , Sous-unité alpha du facteur-1 induit par l'hypoxie/génétique , Lignée cellulaire tumorale , Thérapie moléculaire ciblée , Inhibiteurs de protéines kinases/pharmacologie , StilbènesRÉSUMÉ
Mammalian hibernators survive prolonged periods of cold and resource scarcity by temporarily modulating normal physiological functions, but the mechanisms underlying these adaptations are poorly understood. The hibernation cycle of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) lasts for 5-7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24-48-h periods of an active-like interbout arousal (IBA) state. We show that ground squirrels, who endure the entire hibernation season without food, have negligible hunger during IBAs. These squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons exhibit reduced sensitivity to the orexigenic and anorexigenic effects of ghrelin and leptin, respectively. However, hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia. Our results reveal that thyroid hormone deficiency underlies hibernation anorexia and demonstrate the functional flexibility of the hypothalamic feeding center.
Sujet(s)
Anorexie , Ghréline , Hibernation , Hypothalamus , Sciuridae , Animaux , Hibernation/physiologie , Sciuridae/physiologie , Anorexie/physiopathologie , Anorexie/métabolisme , Hypothalamus/métabolisme , Ghréline/métabolisme , Ghréline/déficit , Leptine/déficit , Leptine/métabolisme , Noyau arqué de l'hypothalamus/métabolisme , Neurones/métabolisme , Neurones/physiologie , Mâle , Hormones thyroïdiennes/métabolisme , Éveil/physiologie , Femelle , Saisons , Comportement alimentaire/physiologieRÉSUMÉ
Leptin has important roles in numerous physiological functions, including those in the regulation of energy balance, and in immune and reproductive systems. However, in the recent years, evidence has implicated it in a number of obesity-related diseases, where its concentrations in serum are significantly elevated. Elevated serum leptin concentrations and increased placental leptin secretion have been reported in women with hypertensive disorders of pregnancy. Whether leptin is responsible for this disorder remains to be established. Leptin injections in healthy rats and mice during pregnancy result in endothelial activation, increased blood pressure and proteinuria. A potential role for leptin in the pathogenesis of pre-eclampsia is hypothesised, particularly in women who are overweight or obese where serum leptin concentrations are often elevated. This review summarises pertinent information in the literature on the role of leptin in puberty, pregnancy, and hypertensive disorders of pregnancy. In particular, the possible mechanism that may be involved in leptin-induced increase in blood pressure and proteinuria during pregnancy and the potential role of marinobufagenin in this disease entity. We hypothesise a significant role for oxidative stress in this, and propose a conceptual framework on the events that lead to endothelial activation, raised blood pressure and proteinuria following leptin administration.
Sujet(s)
Leptine , Leptine/métabolisme , Grossesse , Femelle , Humains , Animaux , Reproduction/physiologie , Hypertension artérielle gravidique/métabolisme , Hypertension artérielle gravidique/physiopathologie , Hypertension artérielle/métabolisme , Hypertension artérielle/physiopathologie , Pression sanguine/physiologie , Pré-éclampsie/métabolisme , Pré-éclampsie/physiopathologieRÉSUMÉ
Organisms experience constant nutritional flux. Mechanisms at the interface of opposing nutritional states-scarcity and surplus-enable organismal energy homeostasis. Contingent on nutritional stores, adipocytes secrete adipokines, such as the fat hormone leptin, to signal nutrient status to the central brain. Increased leptin secretion underlies metabolic dysregulation during common obesity, but the molecular mechanisms regulating leptin secretion from human adipocytes are poorly understood. Here, we report that Atg8/LC3 family proteins, best known for their role in autophagy during nutrient scarcity, play an evolutionarily conserved role during nutrient surplus by promoting adipokine secretion. We show that in a well-fed state, Atg8/LC3 promotes the secretion of the Drosophila functional leptin ortholog unpaired 2 (Upd2) and leptin from human adipocytes. Proteomic analyses reveal that LC3 directs leptin to a secretory pathway in human cells. We identified LC3-dependent extracellular vesicle (EV) loading and secretion (LDELS) as a required step for leptin release, highlighting a unique secretory route adopted by leptin in human adipocytes. In Drosophila, mutations to Upd2's Atg8 interaction motif (AIM) result in constitutive adipokine retention. Atg8-mediated Upd2 retention alters lipid storage and hunger response and rewires the bulk organismal transcriptome in a manner conducive to starvation survival. Thus, Atg8/LC3's bidirectional role in nutrient sensing-conveying nutrient surplus and responding to nutrient deprivation-enables organisms to manage nutrient flux effectively. We posit that decoding how bidirectional molecular switches-such as Atg8/LC3-operate at the nexus of nutritional scarcity and surplus will inform therapeutic strategies to tackle chronic metabolic disorders.
Sujet(s)
Protéines de Drosophila , Drosophila melanogaster , Transduction du signal , Animaux , Humains , Protéines de Drosophila/métabolisme , Protéines de Drosophila/génétique , Drosophila melanogaster/métabolisme , Drosophila melanogaster/génétique , Drosophila melanogaster/physiologie , Adipocytes/métabolisme , Famille de la protéine-8 associée à l'autophagie/métabolisme , Famille de la protéine-8 associée à l'autophagie/génétique , Leptine/métabolisme , Leptine/génétique , Nutriments/métabolisme , Facteurs de transcription/métabolisme , Facteurs de transcription/génétique , Protéines associées aux microtubules/métabolisme , Protéines associées aux microtubules/génétique , AutophagieRÉSUMÉ
BACKGROUND: Craniopharyngioma (CP) is a rare malformational tumor characterized by high rates of recurrence and morbid obesity. However, the role of inflammatory mediators in obesity and the prognosis of patients with CP remains unknown. Therefore, the present study aimed to analyze associations of inflammatory mediators with weight-related outcomes and the prognosis of patients with CP. METHODS: A total of 130 consecutive patients with CP were included in this study. The expression levels of seven inflammatory mediators and the plasma leptin concentration were investigated. Clinical parameters, weight changes, new-onset obesity, and progression-free survival (PFS) were recorded. The relationships between inflammatory mediators, clinicopathologic parameters, weight-related outcomes, and PFS were explored. RESULTS: Compared with those in normal pituitary tissue, the expressions of inflammatory mediators in tumor tissue were higher. Higher expression levels of CXCL1 and CXCL8 were identified as independent risk factors for significant weight gain, and CXCL1 and TNF were identified as independent risk factors for new-onset postoperative obesity. Poor PFS was associated with higher expression levels of CXCL1, CXCL8, IL1A, IL6, and TNF. CONCLUSION: The present study revealed that inflammatory mediators are associated with morbid obesity in patients with CP. Inflammatory mediators may be the critical bridge between elevated leptin and weight-related outcomes. Additionally, PFS was associated with the expression of inflammatory mediators. Further research is needed to elucidate the underlying mechanisms of inflammatory mediators and their potential as targets for novel therapies for CP.
Sujet(s)
Craniopharyngiome , Médiateurs de l'inflammation , Leptine , Tumeurs de l'hypophyse , Survie sans progression , Humains , Craniopharyngiome/métabolisme , Craniopharyngiome/anatomopathologie , Craniopharyngiome/mortalité , Craniopharyngiome/complications , Femelle , Mâle , Adulte , Tumeurs de l'hypophyse/mortalité , Tumeurs de l'hypophyse/métabolisme , Tumeurs de l'hypophyse/anatomopathologie , Tumeurs de l'hypophyse/sang , Adulte d'âge moyen , Médiateurs de l'inflammation/métabolisme , Leptine/sang , Leptine/métabolisme , Pronostic , Obésité/complications , Obésité/métabolisme , Obésité morbide/complications , Obésité morbide/métabolisme , Obésité morbide/mortalité , Jeune adulte , Chimiokine CXCL1/métabolisme , Chimiokine CXCL1/sang , Âge de début , Facteurs de risque , Pertinence clinique , Interleukine-8RÉSUMÉ
The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of the MC3R and the melanocortin system in regulating the response to various anorexigenic agents. The genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness to glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor leptin demonstrated that increased sensitivity to anorectic agents was a generalized result of MC3R antagonism. We observed enhanced neuronal activation in multiple hypothalamic nuclei using Fos IHC following low-dose liraglutide in MC3R-KO mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits that control multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r-/- mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may have value in enhancing the dose-response range of obesity therapeutics.
Sujet(s)
Liraglutide , Récepteur de la mélanocortine de type 3 , Récepteur de la mélanocortine de type 4 , Animaux , Mâle , Souris , Anorexigènes/pharmacologie , Cholécystokinine/métabolisme , Consommation alimentaire/effets des médicaments et des substances chimiques , Glucagon-like peptide 1/métabolisme , Hypothalamus/métabolisme , Leptine/métabolisme , Liraglutide/pharmacologie , Souris de lignée C57BL , Souris knockout , Peptide YY/métabolisme , Peptide YY/génétique , Récepteur de la mélanocortine de type 3/génétique , Récepteur de la mélanocortine de type 3/métabolisme , Récepteur de la mélanocortine de type 3/agonistes , Récepteur de la mélanocortine de type 4/métabolisme , Récepteur de la mélanocortine de type 4/génétique , Récepteur de la mélanocortine de type 4/agonistesRÉSUMÉ
BACKGROUND: Lipodystrophy syndromes are a heterogeneous group of rare, life-limiting diseases characterized by a selective loss of adipose tissue and severe metabolic complications. There is a paucity of information describing the experiences and challenges faced by physicians who have seen and treated patients with lipodystrophy. This study aimed to provide a better understanding of the physician's perspective regarding the patient journey in lipodystrophy, including diagnosis, the burden of disease, and treatment approaches. METHODS: Thirty-three physicians from six countries who had seen or treated patients with lipodystrophy were interviewed using a semi-structured questionnaire. Interviews were transcribed, anonymized, and analyzed for themes and trends. Four main themes were developed: (1) the diagnostic journey in lipodystrophy including the disease features or 'triggers' that result in the onward referral of patients to specialist medical centers with experience in managing lipodystrophy; (2) the impact of lipodystrophy on patient quality of life (QoL); (3) the use of standard therapies and leptin replacement therapy (metreleptin) in lipodystrophy, and (4) barriers to metreleptin use. RESULTS: Participants reported that, due to their rarity and phenotypic heterogeneity, lipodystrophy cases are frequently unrecognized, leading to delays in diagnosis and medical intervention. Early consultation with multidisciplinary specialist medical teams was recommended for suspected lipodystrophy cases. The development and progression of metabolic complications were identified as key triggers for the referral of patients to specialist centers for follow-up care. Participants emphasized the impact of lipodystrophy on patient QoL, including effects on mental health and self-image. Although participants routinely used standard medical therapies to treat specific metabolic complications associated with lipodystrophy, it was acknowledged that metreleptin was typically required in patients with congenital generalized lipodystrophy and in some acquired generalized and partial lipodystrophy cases. A lack of experience among some participants and restrictions to access remained as barriers to metreleptin use. CONCLUSIONS: To our knowledge, this is one of the first studies describing the qualitative experiences of physicians regarding the diagnosis and management of lipodystrophy. Other physician-centered studies may help increase the awareness of lipodystrophy among the wider medical community and support clinical approaches to this rare disease.