GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans

Science, Journal Year: 2024, Volume and Issue: 385(6707), P. 438 - 446

Published: June 27, 2024

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are effective antiobesity drugs. However, the precise central mechanisms of GLP-1RAs remain elusive. We administered to patients with obesity and observed a heightened sense preingestive satiation. Analysis human mouse brain samples pinpointed GLP-1 (GLP-1R) neurons in dorsomedial hypothalamus (DMH) as candidates for encoding Optogenetic manipulation DMH

Language: Английский

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Transforming obesity: The advancement of multi-receptor drugs

Cell, Journal Year: 2024, Volume and Issue: 187(15), P. 3829 - 3853

Published: July 1, 2024

Language: Английский

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The promise of glucagon-like peptide 1 receptor agonists (GLP-1RA) for the treatment of obesity: a look at phase 2 and 3 pipelines

Expert Opinion on Investigational Drugs, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 19

Published: March 1, 2025

Introduction GLP-1-based therapies have changed the treatment of overweight/obesity. Liraglutide 3.0 mg daily, first GLP-1 RA approved for overweight, induced a weight loss 6–8%, Semaglutide 2.4 once weekly improved to about 12–15%, while dual GIP/GLP-1 receptor agonist tirzepatide has 20% in obese people without diabetes.

Language: Английский

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The insulin resistant brain: impact on whole-body metabolism and body fat distribution

Diabetologia, Journal Year: 2024, Volume and Issue: 67(7), P. 1181 - 1191

Published: Feb. 16, 2024

Abstract Insulin exerts its actions not only on peripheral organs but is also transported into the brain where it performs distinct functions in various regions. This review highlights recent advancements our understanding of insulin’s within brain, with a specific emphasis investigations humans. It summarises current knowledge transport insulin brain. Subsequently, showcases robust evidence demonstrating existence and physiological consequences action, while introducing presence resistance pathophysiological condition goes along an impaired acute modulation metabolism response to particularly postprandial state. Furthermore, has been associated long-term adiposity unfavourable adipose tissue distribution, thus implicating pathogenesis subgroups obesity (pre)diabetes that are characterised by patterns body fat distribution. Encouragingly, emerging suggests could represent treatable entity, thereby opening up novel therapeutic avenues improve systemic enhance functions, including cognition. The closes outlook towards prospective research directions aimed at further elucidating clinical implications resistance. emphasises critical need establish feasible diagnostic measures effective interventions. Graphical

Language: Английский

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Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver

Science, Journal Year: 2024, Volume and Issue: 384(6694), P. 438 - 446

Published: April 25, 2024

Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 fission factor (MFFS131). This response was mediated by activation hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFF

Language: Английский

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Neurobiological mechanisms of nicotine's effects on feeding and body weight

Neuroscience & Biobehavioral Reviews, Journal Year: 2025, Volume and Issue: 169, P. 106021 - 106021

Published: Jan. 16, 2025

Language: Английский

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Binding Kinetics, Bias, Receptor Internalization and Effects on Insulin Secretionin vitroandin vivoof a Novel GLP-1R/GIPR Dual Agonist, HISHS-2001

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Abstract The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss type 2 diabetes (T2D) patients. Agonists which bind stimulate multiple receptors have shown particular promise. However, off target effects, including nausea diarrhoea, remain a complication using these agents, modified versions with optimized pharmacological profiles and/or biased signaling at the cognate are increasingly sought. Here, we describe synthesis properties molecule binds glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic polypeptide (GIP) (GLP-1R GIPR) enhance secretion. HISHS-2001 shows increased affinity GLP-1R, well tendency towards reduced internalization recycling this receptor versus FDA-approved dual GLP-1R/GIPR agonist tirzepatide. also displayed significantly greater bias cAMP generation β-arrestin recruitment compared In contrast, G αs was lower tirzepatide but higher GIPR. Administered obese hyperglycaemic db/db mice, circulating whilst lowering body HbA1c similar efficacy substantially doses. Thus, represents novel improved profile.

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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Modulated regulation of the stress-feeding-growth neuroendocrine cascade in Chinese seabass (Lateolabrax maculatus) under temperature and salinity changes

Environmental Research, Journal Year: 2025, Volume and Issue: unknown, P. 121151 - 121151

Published: Feb. 1, 2025

Language: Английский

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Rapid modulation of gut microbiota composition by hypothalamic circuits in mice

Nature Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: April 22, 2025

In recent years, the gut microbiota and derived metabolites have emerged as relevant players in modulating several brain functions, including energy balance control1-3. This form of distant communication mirrors that metabolic hormones (for example, leptin, ghrelin), which convey information about organism's status by exerting effects on diverse regions, master homeostatic centre, hypothalamus4. However, whether hypothalamus is also able to influence composition remains enigmatic. Here we present a study designed unravel this challenging question. To aim, used chemogenetics5 (to selectively activate or inhibit hypothalamic pro-opiomelanocortin agouti-related peptide neurons) centrally administered leptin ghrelin male mice. Subsequently, conducted analysis throughout using 16S rRNA gene sequencing. Our results showed these interventions significantly changed an anatomical short-term (2-4 h) fashion. Transcriptomic indicated changes were associated with reconfiguration neuronal synaptic pathways duodenum concomitant increased sympathetic tone. Interestingly, diet-induced obesity attenuated brain-mediated triggered communities activation. findings reveal previously unanticipated brain-gut axis acutely attunes fast timescales, potential implications for meal-to-meal adjustments systemic control.

Language: Английский

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