Biology subjects

Fleps, S. W.

Publications and source records attributed to Fleps, S. W..

3 recordsLinked to original sources

bioRxiv2024

Incretin hormones and pharmacomimetics rapidly inhibit AgRP neuron activity to suppress appetite

Analogs of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have become mainstays of obesity and diabetes management. However, both the physiologic role of incretin hormones in the control of appetite and the pharmacologic mechanisms by which incretin-mimetic drugs suppress caloric intake remain incompletely understood. Hunger-promoting AgRP-expressing neurons are an important hypothalamic population that regulates food intake. Therefore, we set out to determine how incretins analogs affect their activity in vivo. Using fiber photometry, we observed that both GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) agonism acutely inhibit AgRP neuron activity in fasted mice and reduce the response of AgRP neurons to food. Moreover, optogenetic stimulation of AgRP neurons partially attenuated incretin-induced feeding suppression, suggesting that AgRP neuron inhibition is necessary for the full appetite-suppressing effects of incretin-based therapeutics. Finally, we found that GIP but not GLP-1 is necessary for nutrient-mediated AgRP neuron inhibition, representing a novel physiologic role for GIP in maintaining energy balance. Taken together, these findings reveal neural mechanisms underlying the efficacy of incretin-mimetic obesity therapies. Understanding these drugs mechanisms of action is crucial for the development of next-generation obesity pharmacotherapies with an improved therapeutic profile.

neuroscience↗

bioRxiv2023

Sucrose overconsumption impairs feeding circuit dynamics and promotes palatable food intake

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

neuroscience↗

bioRxiv2022

Selective Nigrostriatal Dopamine Excess Impairs Behaviors Linked to the Cognitive and Negative Symptoms of Psychosis

BACKGROUNDExcess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work for positive symptoms by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms. Further, broadly increasing dopamine release improves cognitive function. These observations fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms, but this has never been tested with dopamine pathway specificity. METHODSWe selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of male and female Trpv1 knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively activate these neurons, validated this approach with fiber photometry, and assessed its effects on social and cognitive function. We combined this manipulation with antipsychotic treatment (haloperidol) and compared the pathway-specific manipulation to treatment with the non-selective dopamine releaser amphetamine. RESULTSSelectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired behavioral processes linked to negative and cognitive symptoms (social drive and working memory). Haloperidol normalized locomotion, only partially rescued working memory, and had no effect on social interaction. By contrast, amphetamine increased locomotion but did not impair social interaction or working memory. CONCLUSIONSExcess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Previous studies using non-selective approaches to release dopamine likely overlooked these contributions of excess dopamine to psychosis. Future therapies should address this disregarded role for excess striatal dopamine in the treatment-resistant symptoms of psychosis.

neuroscience↗