Biology subjects

Phan, B. A.

Publications and source records attributed to Phan, B. A..

4 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↗

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↗