Project description:The function of the central nervous system to regulate food intake can be disrupted by sustained metabolic challenges such as high-fat diet (HFD), which may contribute to the development of various metabolic disorders. In the present study, we found that HFD specifically enhanced food-seeking behavior in fruit flies without altering flies’ baseline metabolism and food consumption. Mechanistically, HFD increased the excitability of a small group of octopaminergic (OA) neurons to a hunger hormone named adipokinetic hormone (AKH), via increasing the accumulation of AKH receptor (AKHR) in these neurons. Upon HFD, excess dietary lipids are transported by a lipoprotein LTP to enter these OA+AKHR+ neurons via the cognate receptor LpR1, which in turn activated AMPK-TOR signaling and suppressed autophagy-dependent degradation of AKHR. Taken together, we uncovered a mechanism that linked HFD, AMPK-TOR signaling, neuronal autophagy, and food-seeking behavior, providing insight in the reshaping of neural circuitry under metabolic challenges and the progression of metabolic diseases.
Project description:The function of the central nervous system to regulate food intake can be disrupted by sustained metabolic challenges such as high-fat diet (HFD), which may contribute to the development of various metabolic disorders. In the present study, we found that HFD specifically enhanced food-seeking behavior in fruit flies without altering flies’ baseline metabolism and food consumption. Mechanistically, HFD increased the excitability of a small group of octopaminergic (OA) neurons to a hunger hormone named adipokinetic hormone (AKH), via increasing the accumulation of AKH receptor (AKHR) in these neurons. Upon HFD, excess dietary lipids are transported by a lipoprotein LTP to enter these OA+AKHR+ neurons via the cognate receptor LpR1, which in turn activated AMPK-TOR signaling and suppressed autophagy-dependent degradation of AKHR. Taken together, we uncovered a mechanism that linked HFD, AMPK-TOR signaling, neuronal autophagy, and food-seeking behavior, providing insight in the reshaping of neural circuitry under metabolic challenges and the progression of metabolic diseases.
Project description:Considering the distinct physiologies of men and women, it stands to reason that they would react differently to solar exposure, but such a study was never conducted before. Here we show that solar exposure induces food-seeking behavior, food intake and weight gain in males, but not in females, by epidemiological analysis, blood-serum proteomics, UVB-exposed mouse behavioral models and human cohort questionnaires . The underlying mechanism entails increased ghrelin secretion from skin adipocytes into the circulation. UVB irradiation led to p53 transcriptional activation of ghrelin in skin adipocytes, with mouse conditional p53-knockout abolishing UVB-induced ghrelin expression and food-seeking behavior. In females, estrogen interferes with the p53–chromatin interaction on the ghrelin promotor, thus blocking ghrelin and, consequently, food-seeking behavior in response to UVB exposure. These results identify the skin as a major mediator of human physiology in furless animals and may lead to therapeutic opportunities for sex-based treatment of endocrine-related diseases.
Project description:Alignment of fasting and feeding with the sleep/wake cycle is coordinated by hypothalamic neurons, though the underlying molecular programs remain incompletely understood. Here we demonstrate that the clock transcription pathway maximizes eating during wakefulness and glucose production during sleep through transcription pathway maximizes eating during autonomous circadian regulation of NPY/AgRP neurons. Tandem profiling of whole cell and ribosome-bound mRNAs in morning and evening under dynamic fasting and fed conditions identified temporal control of activity-dependent gene repertoires in AgRP neurons central to synaptogenesis, bioenergetics, and neurotransmitter and peptidergic signaling. Synaptic and circadian pathways were specific to whole cell RNA analyses, while bioenergetic pathways were selectively enriched in the ribosome-bound transcriptome. Finally, we demonstrate that the AgRP clock mediates the transcriptional food acquisition with sleep/wake state. response to leptin. Our results reveal that time-of-day restriction in transcriptional control of energy-sensing neurons underlies the alignment of hunger and day restriction in transcriptional control of energy-sensing neurons underlies the alignment of hunger and food acquisition with sleep/wake state.
Project description:MicroRNAs are “master regulators” of gene expression. To investigate microRNAs involved in the incentive motivation for cocaine elicited by exposure to cocaine-associated cues, we conducted NanoString nCounter analyses of microRNA expression in the nucleus accumbens shell of male rats that had been tested for cue reactivity in a previous study. These rats had been trained to self-administer cocaine while living in isolate housing, then during a subsequent 21-day forced abstinence period they either stayed under isolate housing or switched to environmental enrichment (EE), as this EE intervention is known to decrease cocaine seeking. This allowed us to create groups of “high” and “low” cocaine seekers using a median split of cocaine-seeking behavior. We conducted a differential expression analysis across these two groups that identified 33 miRNAs that were differentially altered in the nucleus accumbens shell. Predicted mRNA targets of these microRNAs are implicated in synaptic plasticity and neuronal signaling. Some of these microRNAs have previously been implicated in substance use disorders, while others are predicted to target large numbers of cocaine-related genes. Of the 33 differentially expressed microRNAs, 8 were specifically downregulated in the low-seeking group and another set of 8 had expression levels that were significantly correlated with cocaine-seeking. These findings suggest that processes involved in cocaine-seeking behavior may alter, or be altered by, multiple microRNAs. Further research examining the mechanisms involved in these microRNA changes and their effects on signaling may reveal novel therapeutic targets for attenuating drug craving.
Project description:Noncoding RNAs, especially microRNAs (miRNAs) have been implicated in the regulation of neuronal functions, such as learning, cognition and memory formation. However, the particular miRNAs involved in drug-induced behavioral plasticity are largely unknown. Here we report a novel regulator, miR-218, that inhibits heroin-induced behavioral plasticity. Network propagation-based method revealed several miRNAs that play key roles in drug-addiction, among which, miR-218 was decreased in nucleus accumbens (NAc) after chronic exposure to heroin. Lentiviral overexpression of miR-218 in NAc could inhibit heroin-induced reinforcement in both conditioning place preference (CPP) test and heroin self-administration (SA) experiment. Luciferase activity assay indicated miR-218 could regulate neuroplasticity related genes and directly target Mecp2 3’UTR. Consistently, Mecp2-/y mice exhibited reduced heroin seeking behavior in CPP test. These data reveal a functional role of miR-218 and its target, Mecp2, in the regulation of heroin-induced behavioral plasticity.