Biology subjects

Zigman, J.

Publications and source records attributed to Zigman, J..

3 recordsLinked to original sources

bioRxiv2025

MOPRs in mouse islets of Langerhans modulate cell signaling and secretion

Article highlightsO_LIMu opioid receptors are expressed on multiple islets of Langerhans cell types C_LIO_LIMu opioid receptors on islets engage canonical Gi signaling cascades in islets C_LIO_LIMu opioid receptors on islets modulate calcium influx and oscillations C_LIO_LIMu opioid receptors on islets modulate insulin and glucagon secretion. C_LI Most clinically and recreationally used opioids drugs act on the endogenous mu opioid receptor (MOPR). While MOPR is typically studied in the context of addiction and analgesia, decades of evidence indicates that they have a strong modulatory role on metabolism and glycemia. However, whether these effects are directly driven by MOPR actions on pancreatic islets remains poorly understood. Here we sought to comprehensively profile MOPRs on islets to assess how their activity shapes cellular physiology and secretion. First, we used RNA-seq, fluorescent in situ hybridization, and immunoblotting approaches to map islet expression. We observed robust expression of MOPR across multiple cell types in islets. Next, using a FRET-based approach, we show that MOPRs recruit canonical inhibitory pathways, reducing cAMP accumulation. Correspondingly, islets from constitutive MOPR knockout mice showed increased calcium influx and oscillations. However, MOPR knockout had no effect on insulin secretion, instead increase glucagon secretion. Surprisingly, while MOPR antagonism increased overall calcium, it reduced calcium oscillations and suppressed insulin secretion. By contrast MOPR agonism suppressed calcium, increased oscillations, and had no effect on overall hormone secretion. Collectively, these results suggest that MOPR can profoundly shape islet activity, with these effects likely driven by their actions on distinct cell types.

pharmacology and toxicology↗

bioRxiv2023

Ghrelin signalling in AgRP neurons links metabolic state to the sensory regulation of AgRP neural activity.

ObjectiveThe sensory detection of food and food cues suppresses Agouti related peptide (AgRP) neuronal activity prior to consumption with greatest suppression in response to high caloric food or energy need. Although external sensory cues regulate AgRP neuronal activity, the interoceptive mechanisms priming an appropriate AgRP neural response to sensory information of caloric availability remain unexplored. Since hunger increases plasma ghrelin, we hypothesized that ghrelin receptor (GHSR) signalling on AgRP neurons is a key interoceptive mechanism integrating energy need with external sensory cues predicting caloric availability. MethodsWe used in vivo photometry to measure the effects of ghrelin administration or fasting on AgRP neural activity with GCaMP6s and dopamine release in the nucleus accumbens with GRAB-DA in mice lacking ghrelin receptors in AgRP neurons. ResultsThe deletion of GHSR on AgRP neurons prevented ghrelin-induced food intake, motivation and AgRP activity. The presentation of food (peanut butter pellet) or a wooden dowel suppressed AgRP activity in fasted WT but not mice lacking GHSRs in AgRP neurons. Similarly, peanut butter and a wooden dowel increased dopamine release in the nucleus accumbens after ip ghrelin injection in WT but not mice lacking GHSRs in AgRP neurons. No difference in dopamine release was observed in fasted mice. Finally, ip ghrelin administration did not directly increase dopamine neural activity in the ventral tegmental area. ConclusionsOur results suggest that AgRP GHSRs integrate an interoceptive state of energy need with external sensory information to produce an optimal change in AgRP neural activity. Thus, ghrelin signalling on AgRP neurons is more than just a feedback signal to increase AgRP activity during hunger.

neuroscience↗

bioRxiv2023

Hunger signalling in the olfactory bulb primes exploration, food-seeking and peripheral metabolism.

Growing evidence highlights a complex interaction between olfaction and metabolism with impaired olfactory function observed in obesity and increased olfactory sensitivity during hunger. The mechanisms linking metabolic state and olfaction remain unknown, but increased accessibility of hormones, such as ghrelin, and the diverse expression of hormone receptors such as those for ghrelin (GHSRs) in the olfactory system suggests an underappreciated neuroendocrine role. Here, we examined the hypothesis that GHSRs in the olfactory bulb (OB) link hunger with olfactory sensitivity to influence foraging behaviours and metabolism. Selective deletion of OBGHSRs in adult male mice was achieved with adeno-associated viral expression of cre-recombinase in the OB of floxed-Ghsr mice. OBGHSR deletion significantly affected olfactory discrimination and habituation to both food and pheromone odours, with greatest effect under fasted conditions. Anxiety-like and depression-like behaviour was significantly greater after OBGHSR deletion using 3 independent anxiety behavioural tasks and testing for anhedonia, whereas exploratory behaviour was reduced. No effect on spatial navigation and memory was observed. Although OBGHSR deletion did not affect cumulative food intake, it significantly impacted feeding behaviour as evidenced by altered bout number and duration. Moreover, food-finding after fasting or ip ghrelin was attenuated. Intriguingly, OBGHSR deletion caused an increase in body weight and fat mass, spared fat utilisation on a chow diet and impaired glucose metabolism indicating metabolic dysfunction. We conclude that OBGHSRs maintain olfactory sensitivity, particularly during hunger, and facilitate behavioural adaptations that optimise food-seeking in anxiogenic environments, priming metabolic pathways in preparation for food consumption.

neuroscience↗