Biology subjects

Schwartz, M. W.

Publications and source records attributed to Schwartz, M. W..

7 recordsLinked to original sources

bioRxiv2026

Central Glucagon-Like Peptide-1 Agonism Ameliorates Colonic Inflammation in a Murine Model of Inflammatory Bowel Disease

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the treatment of obesity and type 2 diabetes (T2D). These drugs also have anti-inflammatory effects that have recently been extended to the treatment of inflammatory bowel disease (IBD). Whether the mechanism underlying this benefit involves a direct action on the intestine or instead is mediated via GLP-1Rs in the brain, however, is unknown. Based on evidence implicating the brain as the target for the anti-obesity and anti-inflammatory effects of GLP-1RAs, we sought to determine if central GLP-1R signaling is sufficient to explain its intestinal anti-inflammatory effects. To this end, we compared the efficacy of peripheral vs central administration of the GLP-1RA, semaglutide (SEMA), in diet-induced obese (DIO) mice with dextran sodium sulfate (DSS)-induced colitis. We report that compared to vehicle, both colitis severity and histopathological injury following DSS administration are reduced by peripheral administration of SEMA. We also report that this benefit is largely recapitulated by intracerebroventricular administration of SEMA at a low dose that, when administered peripherally, is below that needed to affect food intake and body weight. We conclude that in a mouse model of colitis, activation of GLP-1Rs in the brain is sufficient to explain the intestinal anti-inflammatory effect conferred by GLP-1R agonism.

neuroscience↗

bioRxiv2026

AgRP Neuron Activity Predicts and Tracks the Glycemic Response to Oral Glucose

Hypothalamic AgRP neurons are uniquely responsive to nutritional cues and play an important role in fuel homeostasis. To investigate the temporal relationship between the activity of these neurons and the glycemic response to an oral glucose load, we simultaneously monitored AgRP neuron activity (by fiber photometry in AgRP-IRES-cre mice) and the arterial glucose level, both before and after oral gavage (OG) of either water or glucose (0.5-2.5 g/kg). We report that the AgRP neuron response to an OG glucose load can be subdivided into two functionally distinct phases - one that begins prior to glucose delivery and a second that extends from peak inhibition through the return towards baseline. The first phase appears to be anticipatory in nature and is also predictive of subsequent changes in glycemia, suggesting a role in the handling of an oral glucose load. To analyze the relationship between the second phase response and changes of glycemia, we employed a model that allows residual activity to be removed subsequent to the first phase component. This analysis reveals that unlike the first phase, the degree of residual inhibition - the second phase - tracks the glycemic response. Moreover, this response is temporally aligned with the blood glucose (BG) rate of change (which is predictive of future BG levels), with AgRP neurons lagging BG rate of change by ~5 minutes. We conclude that the AgRP neuron response to an oral glucose challenge consists of two distinct phases, each with its own determinants and metabolic implications: an initial anticipatory component that is predictive of the subsequent glycemic response, and a second phase that tracks the rate of BG change.

neuroscience↗

bioRxiv2026

A uniquely leptin sensitive hypothalamic neuron population limits hyperphagia and weight gain in diet-induced obesity

Despite widespread loss of leptin responsiveness in obesity, endogenous leptin continues to restrain feeding, yet the neural substrates that remain sensitive and mediate this effect are unknown. Combining spatial transcriptomics with single-nucleus RNA sequencing in mice with diet-induced obesity (DIO), we show that while most hypothalamic leptin receptor (Lepr) neurons minimally respond to elevated leptin, a single population defined by glucagon-like peptide-1 receptor (Glp1r) co-expression retains robust leptin sensitivity. These Lepr/Glp1r neurons project onto and restrain orexigenic Agrp neurons. Lepr deletion from Lepr/Glp1r neurons blocks the anorectic effect of exogenous leptin, reinstates hyperphagic responses normally suppressed in DIO, amplifies the obesogenic response to palatable diet, and unexpectedly attenuates hypothalamic microglial activation- a hallmark of DIO previously attributed to diet rather than leptin signaling. Hence, preserved leptin action through a single neuronal population governs downstream circuit activity to limit hyperphagia and weight gain during obesity.

molecular biology↗

bioRxiv2025

Sex differences in GLP-1 signaling across species

Two billion humans are currently overweight or obese1. While glucagon-like peptide 1 receptor (GLP1R) agonists have emerged as the most promising treatment for this epidemic, side effects including nausea and vomiting constitute a significant obstacle to their use. Of the patients currently being treated, women represent nearly 70%. While early studies have noted sex differences in the response to these drugs, the nature of these differences remain poorly characterized. Using real world electronic medical record (EMR) data, we find that women experience more than double the rates of persistent nausea and vomiting when prescribed GLP1R agonists. To investigate this sex difference in greater detail, we developed novel, species-specific in vivo phenomic assays to quantify aversive behaviors. In both mice and rats, aversive responses to either semaglutide or tirzepatide were greater in females than males. To investigate the basis for this difference, we constructed a mouse single cell transcriptomic atlas of body and brain regions most relevant to the action of GLP-1. Using this atlas we find that multiple neuronal cell types involved in the processing of aversive stimuli and nausea had higher GLP1R expression in females than males. Heightened susceptibility of females to the aversive effects of GLP1R agonists could therefore involve increased activation of these brain circuits. Finally, we demonstrate that in mice, both the efficacy and tolerability of GLP1R agonists vary with the phase of the estrous cycle, being highest during proestrus (when estrogen levels peak) and lowest in diestrus (low estrogen levels). Similarly, we report that higher circulating estrogen levels in humans is associated with heightened risk of nausea and vomiting among women taking a GLP1R agonist. Based on these findings, we anticipate that women will continue to be disproportionately impacted by the adverse effects associated with all members of this drug class. Research to better understand and ultimately mitigate this heightened susceptibility is an important priority for new drug development in this area, and novel approaches to model the impact of endogenous hormone signaling will be critical to developing better treatments for more people.

systems biology↗

bioRxiv2020

Role of hypothalamic MAPK/ERK signaling in diabetes remission induced by the central action of fibroblast growth factor 1

The capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that following icv FGF1 injection, hypothalamic signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family is induced for at least 24h. Further, we show that in diabetic Lepob/ob mice, this prolonged response is required for the sustained antidiabetic action of FGF1, since it is abolished by sustained (but not acute) pharmacologic blockade of hypothalamic MAPK/ERK signaling. We also demonstrate that FGF1 R50E, a FGF1 mutant that activates FGF receptors but induces only transient hypothalamic MAPK/ERK signaling, fails to mimic the sustained glucose lowering induced by FGF1. These data identify sustained activation of hypothalamic MAPK/ERK signaling as playing an essential role in the mechanism underlying diabetes remission induced by icv FGF1 administration.

neuroscience↗

bioRxiv2020

Leptin-receptor neurons in the dorsomedial hypothalamus regulate the timing of circadian rhythms in feeding and metabolism in mice

Animal behavior and metabolism are tightly coordinated with sleep-wake cycles governed by the brain in harmony with environmental light:dark cycles. Within the brain, the dorsomedial hypothalamic nucleus (DMH) has been implicated in the integrative control of feeding, energy homeostasis, and circadian rhythms [1], but the underlying cell types are unknown. Here, we identify a role for DMH leptin receptor-expressing neurons (DMHLepR) in these effects. Using a viral approach, we show that silencing DMHLepR neurons in adult mice not only increases body weight and adiposity, but also shifts circadian rhythms in feeding and metabolism into the light-cycle. Moreover, DMHLepR silencing abolishes the normal increase in dark-cycle locomotor activity characteristic of nocturnal rodents. Furthermore, DMHLepR-silenced mice fail to entrain to a restrictive change in food availability. Together, these findings identify DMHLepR neurons as critical determinants of the daily time of feeding and associated metabolic rhythms.

neuroscience↗

bioRxiv2020

Cold-induced hyperphagia requires AgRP-neuron activation in mice

To maintain energy homeostasis during cold exposure, the increased energy demands of thermogenesis must be counterbalanced by increased energy intake. To investigate the neurobiological mechanisms underlying this cold-induced hyperphagia, we asked whether agouti-related peptide (AgRP) neurons are activated when animals are placed in a cold environment and, if so, whether this response is required for the associated hyperphagia. We report that AgRP-neuron activation occurs rapidly upon acute cold exposure, as do increases of both energy expenditure and energy intake, suggesting the mere perception of cold is sufficient to engage each of these responses. We further report that silencing of AgRP neurons selectively blocks the effect of cold exposure to increase food intake. Together, these findings establish a physiologically important role for AgRP neurons in the hyperphagic response to cold exposure.

neuroscience↗