Reduced Liver Mitochondrial Energy Metabolism Impairs Food Intake Regulation Following Gastric Preloads and Fasting.

The capacity of the liver to serve as a peripheral sensor in the regulation of food intake has been debated for over half a century. The anatomical position and physiological roles of the liver suggest it is a prime candidate to serve as an interoceptive sensor of peripheral tissue and systemic energy state. Importantly, maintenance of liver ATP levels and within-meal food intake inhibition is impaired in human subjects with obesity and obese pre-clinical models.

Hepatic vagal afferents convey clock-dependent signals to regulate circadian food intake.

Circadian desynchrony induced by shiftwork or jet lag is detrimental to metabolic health, but how synchronous or desynchronous signals are transmitted among tissues is unknown. We report that liver molecular clock dysfunction is signaled to the brain through the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain.

Hepatic Vagal Afferents Convey Clock-Dependent Signals to Regulate Circadian Food Intake.

Unlabelled: Circadian desynchrony induced by shiftwork or jetlag is detrimental to metabolic health, but how synchronous/desynchronous signals are transmitted among tissues is unknown. Here we report that liver molecular clock dysfunction is signaled to the brain via the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain.

Amylin Modulates a Ventral Tegmental Area-to-Medial Prefrontal Cortex Circuit to Suppress Food Intake and Impulsive Food-Directed Behavior.

Background: A better understanding of the neural mechanisms regulating impaired satiety to palatable foods is essential to treat hyperphagia linked with obesity. The satiation hormone amylin signals centrally at multiple nuclei including the ventral tegmental area (VTA). VTA-to-medial prefrontal cortex (mPFC) projections encode food reward information to influence behaviors including impulsivity.

Metabolic hormone action in the VTA: Reward-directed behavior and mechanistic insights.

Dysfunctional signaling in midbrain reward circuits perpetuates diseases characterized by compulsive overconsumption of rewarding substances such as substance abuse, binge eating disorder, and obesity. Ventral tegmental area (VTA) dopaminergic activity serves as an index for how rewarding stimuli are perceived and triggers behaviors necessary to obtain future rewards. The evolutionary linking of reward with seeking and consuming palatable foods ensured an organism's survival, and hormone systems that regulate appetite concomitantly developed to regulate motivated behaviors.

Tirzepatide suppresses palatable food intake by selectively reducing preference for fat in rodents.

Aim: To investigate the role of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists alone or combined with glucagon-like peptide-1 receptor (GLP-1R) agonists to regulate palatable food intake and the role of specific macronutrients in these preferences.

Methods: To understand this regulation, we treated mice and rats on several choice diet paradigms of chow and a palatable food option with individual or dual GIPR and GLP-1R agonists.

Results: In mice, the dual agonist tirzepatide suppressed total caloric intake, while promoting the intake of chow over a high fat/sucrose diet.

REV-ERB nuclear receptors in the suprachiasmatic nucleus control circadian period and restrict diet-induced obesity.

Circadian disruption, as occurs in shift work, is associated with metabolic diseases often attributed to a discordance between internal clocks and environmental timekeepers. REV-ERB nuclear receptors are key components of the molecular clock, but their specific role in the SCN master clock is unknown. We report here that mice lacking circadian REV-ERB nuclear receptors in the SCN maintain free-running locomotor and metabolic rhythms, but these rhythms are notably shortened by 3 hours.

GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models.

Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.

Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release.

Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia.

A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity.

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide.

The Role of GPR109a Signaling in Niacin Induced Effects on Fed and Fasted Hepatic Metabolism.

Signaling through GPR109a, the putative receptor for the endogenous ligand β-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles.

Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice.

Obesity occurs when energy expenditure is outweighed by energy intake. Tuberal hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), control food intake and energy expenditure. Here we report that, in contrast with females, male mice lacking circadian nuclear receptors REV-ERBα and -β in the tuberal hypothalamus (HDKO mice) gained excessive weight on an obesogenic high-fat diet due to both decreased energy expenditure and increased food intake during the light phase.

Role of ketone signaling in the hepatic response to fasting.

Ketosis is a metabolic adaptation to fasting, nonalcoholic fatty liver disease (NAFLD), and prolonged exercise. β-OH butyrate acts as a transcriptional regulator and at G protein-coupled receptors to modulate cellular signaling pathways in a hormone-like manner. While physiological ketosis is often adaptive, chronic hyperketonemia may contribute to the metabolic dysfunction of NAFLD.

Non-Mammalian Vertebrates: Distinct Models to Assess the Role of Ion Gradients in Energy Expenditure.

Animals store metabolic energy as electrochemical gradients. At least 50% of mammalian energy is expended to maintain electrochemical gradients across the inner mitochondrial membrane (H), the sarcoplasmic reticulum (Ca), and the plasma membrane (Na/K). The potential energy of these gradients can be used to perform work (e.

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones.

Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis.

Temporal delays among place cells determine the frequency of population theta oscillations in the hippocampus.

Driven either by external landmarks or by internal dynamics, hippocampal neurons form sequences of cell assemblies. The coordinated firing of these active cells is organized by the prominent "theta" oscillations in the local field potential (LFP): place cells discharge at progressively earlier theta phases as the rat crosses the respective place field ("phase precession"). The faster oscillation frequency of active neurons and the slower theta LFP, underlying phase precession, creates a paradox.

The dynamical response properties of neocortical neurons to temporally modulated noisy inputs in vitro.

Cortical neurons are often classified by current-frequency relationship. Such a static description is inadequate to interpret neuronal responses to time-varying stimuli. Theoretical studies suggested that single-cell dynamical response properties are necessary to interpret ensemble responses to fast input transients.

Hippocampal place cell assemblies are speed-controlled oscillators.

The phase of spikes of hippocampal pyramidal cells relative to the local field theta oscillation shifts forward ("phase precession") over a full theta cycle as the animal crosses the cell's receptive field ("place field"). The linear relationship between the phase of the spikes and the travel distance within the place field is independent of the animal's running speed. This invariance of the phase-distance relationship is likely to be important for coordinated activity of hippocampal cells and space coding, yet the mechanism responsible for it is not known.

Contributions of intrinsic membrane dynamics to fast network oscillations with irregular neuronal discharges.

During fast oscillations in the local field potential (40-100 Hz gamma, 100-200 Hz sharp-wave ripples) single cortical neurons typically fire irregularly at rates that are much lower than the oscillation frequency. Recent computational studies have provided a mathematical description of such fast oscillations, using the leaky integrate-and-fire (LIF) neuron model. Here, we extend this theoretical framework to populations of more realistic Hodgkin-Huxley-type conductance-based neurons.

Interneuron Diversity series: Circuit complexity and axon wiring economy of cortical interneurons.

The performance of the brain is constrained by wiring length and maintenance costs. The apparently inverse relationship between number of neurons in the various interneuron classes and the spatial extent of their axon trees suggests a mathematically definable organization, reminiscent of 'small-world' or scale-free networks observed in other complex systems. The wiring-economy-based classification of cortical inhibitory interneurons is supported by the distinct physiological patterns of class members in the intact brain.