Integrative neurocircuits that control metabolism and food intake

Science, Journal Year: 2023, Volume and Issue: 381(6665)

Published: Sept. 28, 2023

Systemic metabolism has to be constantly adjusted the variance of food intake and even prepared for anticipated changes in nutrient availability. Therefore, brain integrates multiple homeostatic signals with numerous cues that predict future deviations energy supply. Recently, our understanding neural pathways underlying these regulatory principles-as well as their convergence hypothalamus key coordinator intake, expenditure, glucose metabolism-have been revealed. These advances have changed view brain-dependent control metabolic physiology. In this Review, we discuss new concepts about how alterations contribute development prevalent diseases such obesity type 2 diabetes mellitus emerging knowledge may provide targets treatment.

Language: Английский

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GLP-1-directed NMDA receptor antagonism for obesity treatment

Nature, Journal Year: 2024, Volume and Issue: 629(8014), P. 1133 - 1141

Published: May 15, 2024

The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that critical to many processes in the brain. Genome-wide association studies suggest glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis

Language: Английский

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Thalamic opioids from POMC satiety neurons switch on sugar appetite

Science, Journal Year: 2025, Volume and Issue: 387(6735), P. 750 - 758

Published: Jan. 2, 2025

High sugar–containing foods are readily consumed, even after meals and beyond fullness sensation (e.g., as desserts). Although reward-driven processing of palatable can promote overeating, the neurobiological mechanisms that underlie selective appetite for sugar in states satiety remain unclear. Hypothalamic pro-opiomelanocortin (POMC) neurons principal regulators because they decrease food intake through excitatory melanocortin neuropeptides. We discovered POMC not only fed conditions but concomitantly switch on appetite, which drives overconsumption. neuron projections to paraventricular thalamus selectively inhibited postsynaptic mu-opioid receptor signaling. This opioid circuit was strongly activated during consumption, most notable states. Correspondingly, inhibiting its activity diminished high-sugar diet sated mice.

Language: Английский

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Long‐term impact of obesity: Unraveling adipose epigenetic memory

Clinical and Translational Medicine, Journal Year: 2025, Volume and Issue: 15(3)

Published: March 1, 2025

Language: Английский

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Sucrose overconsumption impairs AgRP neuron dynamics and promotes palatable food intake

Cell Reports, Journal Year: 2024, Volume and Issue: 43(2), P. 113675 - 113675

Published: Jan. 14, 2024

Rapid gut-brain communication is critical to maintain energy balance and disrupted in diet-induced obesity. In particular, the role of carbohydrate overconsumption regulation interoceptive circuits vivo requires further investigation. Here, we report that an obesogenic high-sucrose diet (HSD) selectively blunts silencing hunger-promoting agouti-related protein (AgRP) neurons following intragastric delivery glucose, whereas previously showed a high-fat (HFD) attenuates lipid-induced neural silencing. By contrast, both HSD HFD reversibly dampen rapid AgRP neuron inhibition chow presentation promote intake more palatable foods. Our findings reveal excess sugar fat pathologically modulate feeding circuit activity macronutrient-dependent -independent ways thus may additively exacerbate

Language: Английский

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Parallel gut-to-brain pathways orchestrate feeding behaviors

Nature Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 3, 2024

Language: Английский

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Bone marrow immune cells respond to fluctuating nutritional stress to constrain weight regain

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(11), P. 1915 - 1930.e8

Published: Sept. 12, 2023

Language: Английский

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Melanocortin-3 receptor expression in AgRP neurons is required for normal activation of the neurons in response to energy deficiency

Cell Reports, Journal Year: 2023, Volume and Issue: 42(10), P. 113188 - 113188

Published: Oct. 1, 2023

The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on agouti-related protein (AgRP) nerve terminals, from where it regulates GABA release onto secondary MC4R-expressing neurons. However, MC3R knockout (KO) mice also exhibit defective behavioral and neuroendocrine responses to fasting. Here, we demonstrate that KO activation AgRP neurons in response fasting, cold exposure, or ghrelin while exhibiting normal inhibition by sensory detection food ad libitum-fed state. Using conditional model, show control neuron fasting requires specific presence within Thus, crucial player responsiveness soma both hormonal neuronal signals energy need.

Language: Английский

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Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment

Science Advances, Journal Year: 2024, Volume and Issue: 10(9)

Published: March 1, 2024

Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we use UK Biobank GWAS summary statistics of mass index (BMI) fat percentage (BF%) to identify genes encoding proteins known interact with postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) N -methyl- d -aspartate (NMDA) receptors. Loci in/near discs large homolog 4 ( DLG4 ) protein interacting C kinase 1 PICK1 reached significance P < 5 × 10 − 8 BF% and/or BMI. To further evaluate the density protein-95 (PSD-95; gene name: energy homeostasis, used dimeric PSD-95/disc large/ZO-1 (PDZ) domain–targeting peptides PSD-95 demonstrate that pharmacological inhibition induces prolonged weight-lowering effects obese mice. Collectively, these data scaffolding proteins, PSD-95, are genetically linked obesity targeting their PDZ domains represents promising therapeutic avenue sustained loss.

Language: Английский

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GABAergic disinhibition from the BNST to PNOCARC neurons promotes HFD-induced hyperphagia

Cell Reports, Journal Year: 2024, Volume and Issue: 43(6), P. 114343 - 114343

Published: June 1, 2024

Activation of prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus (ARC) promotes high-fat-diet (HFD)-induced hyperphagia. In turn, PNOCARC can inhibit anorexic response proopiomelanocortin (POMC) neurons. Here, we validate necessity activity for HFD-induced inhibition POMC mice and find that PNOCARC-neuron-dependent is mediated by gamma-aminobutyric acid (GABA) release. When monitoring individual neuron via Ca2+ imaging, a subpopulation inhibited upon gastrointestinal calorie sensing disinhibited HFD feeding. Combining retrograde rabies tracing circuit mapping, PNOC from bed stria terminalis (PNOCBNST) provide inhibitory input to neurons, this blunted This work sheds light on how an increase caloric content diet rewire neuronal circuit, paving way overconsumption obesity development.

Language: Английский

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