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1.
Nat Metab ; 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-39030389

ABSTRACT

Dysbiosis of the gut microbiota has been implicated in the pathogenesis of metabolic syndrome (MetS) and may impair host metabolism through harmful metabolites. Here, we show that Desulfovibrio, an intestinal symbiont enriched in patients with MetS, suppresses the production of the gut hormone glucagon-like peptide 1 (GLP-1) through the production of hydrogen sulfide (H2S) in male mice. Desulfovibrio-derived H2S is found to inhibit mitochondrial respiration and induce the unfolded protein response in intestinal L cells, thereby hindering GLP-1 secretion and gene expression. Remarkably, blocking Desulfovibrio and H2S with an over-the-counter drug, bismuth subsalicylate, improves GLP-1 production and ameliorates diet-induced metabolic disorder in male mice. Together, our study uncovers that Desulfovibrio-derived H2S compromises GLP-1 production, shedding light on the gut-relayed mechanisms by which harmful microbiota-derived metabolites impair host metabolism in MetS and suggesting new possibilities for treating MetS.

2.
Nat Rev Endocrinol ; 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39054359

ABSTRACT

Food intake and energy expenditure are sensed and processed by multiple brain centres to uphold energy homeostasis. Evidence from the past decade points to the brain vasculature as a new critical player in regulating energy balance that functions in close association with the local neuronal networks. Nutritional imbalances alter many properties of the neurovascular system (such as neurovascular coupling and blood-brain barrier permeability), thus suggesting a bidirectional link between the nutritional milieu and neurovascular health. Increasing numbers of people are consuming a Western diet (comprising ultra-processed food with high-fat and high-sugar content) and have a sedentary lifestyle, with these factors contributing to the current obesity epidemic. Emerging pharmacological interventions (for example, glucagon-like peptide 1 receptor agonists) successfully trigger weight loss. However, whether these approaches can reverse the detrimental effects of long-term exposure to the Western diet (such as neurovascular uncoupling, neuroinflammation and blood-brain barrier disruption) and maintain stable body weight in the long-term needs to be clarified in addition to possible adverse effects. Lifestyle interventions revert the nutritional trigger for obesity and positively affect our overall health, including the cardiovascular system. This Perspective examines how lifestyle interventions affect the neurovascular system and neuronal networks.

3.
Physiology (Bethesda) ; 39(4): 0, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38536114

ABSTRACT

Whether it is the dramatic suffocating sensation from a heat wave in the summer or the positive reinforcement arising from a hot drink on a cold day; we can certainly agree that our thermal environment underlies our daily rhythms of sensation. Extensive research has focused on deciphering the central circuits responsible for conveying the impact of thermogenesis on mammalian behavior. Here, we revise the recent literature responsible for defining the behavioral correlates that arise from thermogenic fluctuations in mammals. We transition from the physiological significance of thermosensation to the circuitry responsible for the autonomic or behavioral responses associated with it. Subsequently, we delve into the positive and negative valence encoded by thermoregulatory processes. Importantly, we emphasize the crucial junctures where reward, pain, and thermoregulation intersect, unveiling a complex interplay within these neural circuits. Finally, we briefly outline fundamental questions that are pending to be addressed in the field. Fully deciphering the thermoregulatory circuitry in mammals will have far-reaching medical implications. For instance, it may lead to the identification of novel targets to overcome thermal pain or allow the maintenance of our core temperature in prolonged surgeries.


Subject(s)
Body Temperature Regulation , Brain , Cues , Thermosensing , Humans , Animals , Thermosensing/physiology , Brain/physiology , Body Temperature Regulation/physiology , Pain/physiopathology , Thermogenesis/physiology
4.
Trends Mol Med ; 29(10): 786-788, 2023 10.
Article in English | MEDLINE | ID: mdl-37487781

ABSTRACT

Brain vasculature is chiefly considered a support network responsible for delivering signaling molecules and nutrients to neural cells. Several central disorders exhibit disruptions in functional and structural plasticity of this network. Considering this vasculature as structurally dynamic, it challenges the field's view and may be important for brain-directed therapeutic strategies.


Subject(s)
Blood-Brain Barrier , Brain , Humans , Neurons
5.
Glia ; 71(8): 1906-1920, 2023 08.
Article in English | MEDLINE | ID: mdl-37017183

ABSTRACT

Microglia participates in the modulation of pain signaling. The activation of microglia is suggested to play an important role in affective disorders that are related to a dysfunction of the mesocorticolimbic system (MCLS) and are commonly associated with chronic pain. Moreover, there is evidence that mu-opioid receptors (MORs), expressed in the MCLS, are involved in neuroinflammatory events, although the way by which they do it remains to be elucidated. In this study, we propose that MOR pharmacological activation within the MCLS activates and triggers the local release of proinflammatory cytokines and this pattern of activation is impacted by the presence of systemic inflammatory pain. To test this hypothesis, we used in vivo microdialysis coupled with flow cytometry to measure cytokines release in the nucleus accumbens and immunofluorescence of IBA1 in areas of the MCLS on a rat model of inflammatory pain. Interestingly, the treatment with DAMGO, a MOR agonist locally in the nucleus accumbens, triggered the release of the IL1α, IL1ß, and IL6 proinflammatory cytokines. Furthermore, MOR pharmacological activation in the ventral tegmental area (VTA) modified the levels of IBA1-positive cells in the VTA, prefrontal cortex, the nucleus accumbens and the amygdala in a dose-dependent way, without impacting mechanical nociception. Additionally, MOR blockade in the VTA prevents DAMGO-induced effects. Finally, we observed that systemic inflammatory pain altered the IBA1 immunostaining derived from MOR activation in the MSCLS. Altogether, our results indicate that the microglia-MOR relationship could be pivotal to unravel some inflammatory pain-induced comorbidities related to MCLS dysfunction.


Subject(s)
Chronic Pain , Microglia , Neuroinflammatory Diseases , Prefrontal Cortex , Receptors, Opioid, mu , Ventral Tegmental Area , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/metabolism , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/physiopathology , Microglia/metabolism , Ventral Tegmental Area/metabolism , Ventral Tegmental Area/physiopathology , Prefrontal Cortex/metabolism , Prefrontal Cortex/physiopathology , Animals , Rats , Disease Models, Animal , Chronic Pain/metabolism , Chronic Pain/physiopathology , Nucleus Accumbens/metabolism , Nucleus Accumbens/physiopathology , Calcium-Binding Proteins/metabolism , Microfilament Proteins/metabolism , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Male , Female , Rats, Sprague-Dawley
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