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ObjectiveActivation of vagal afferent neurons (VAN) by postprandial gastrointestinal signals terminates feeding and facilitates nutrient digestion and absorption. Leptin modulates responsiveness of VAN to meal-related gastrointestinal signals. Rodents with high-fat diet (HF) feeding develop leptin resistance that impairs responsiveness of VAN. We hypothesized that lack of leptin signaling in VAN reduces responses to meal-related signals, which in turn decreases absorption of nutrients and energy storage from high-fat, calorically dense food.MethodsMice with conditional deletion of the leptin receptor from VAN (Nav1.8-Cre/LepRfl/fl; KO) were used in this study. Six-week-old male mice were fed a 45% HF for 4 weeks; metabolic phenotype, food intake, and energy expenditure were measured. Absorption and storage of nutrients were investigated in the refed state.ResultsAfter 4 weeks of HF feeding, KO mice gained less body weight and fat mass that WT controls, but this was not due to differences in food intake or energy expenditure. KO mice had reduced expression of carbohydrate transporters and absorption of carbohydrate in the jejunum. KO mice had fewer hepatic lipid droplets and decreased expression of de novo lipogenesis-associated enzymes and lipoproteins for endogenous lipoprotein pathway in liver, suggesting decreased long-term storage of carbohydrate in KO mice.ConclusionsImpairment of leptin signaling in VAN reduces responsiveness to gastrointestinal signals, which reduces intestinal absorption of carbohydrates and de novo lipogenesis resulting in reduced long-term energy storage. This study reveals a novel role of vagal afferents to support digestion and energy storage that may contribute to the effectiveness of vagal blockade to induce weight loss.

Cognitive dysfunction is frequently reported in individuals with postural orthostatic tachycardia syndrome (POTS), possibly resulting from reduced cerebral blood flow (CBF). We used brain SPECT, an accessible imaging modality that has not been systematically evaluated in this patient group. Retrospective review of participants from our registry was undertaken to identify those who had a brain SPECT performed for investigation of cognitive dysfunction. Abnormal CBF was taken as z-score > 2 standard deviations of healthy control reference values. Patient reported outcome measures (PROMs) such as autonomic, gastric and quality of life symptom scores were analyzed. From a total of 56 participants (mean 34.8 ± 10.7 years, 88% females), PROMs indicate: moderate to severe autonomic dysfunction in 75%; at least mild to moderate gastroparesis in 23%; low global health rating and utility scores. Abnormal CBF was seen in 61% but did not differ by POTS triggers. The regions with the lowest mean z-scores were the lateral prefrontal and sensorimotor cortices. Hierarchal regression analyses found number of brain regions with abnormal CBF, autonomic and gastric symptoms to account for 51% of variances in health utility. Cerebral hypoperfusion is prevalent in those with POTS and cognitive dysfunction even whilst supine, contributing to reduced quality of life. [ABSTRACT FROM AUTHOR]

Food intake and activity adapt during pregnancy to meet the increased energy demands. In comparison to non‐pregnant females, pregnant mice consume more food, eating larger meals during the light phase, and reduce physical activity. How pregnancy changes the circadian timing of behaviour was less clear. We therefore randomised female C57BL/6J mice to mating for study until early (n = 10), mid‐ (n = 10) or late pregnancy (n = 11) or as age‐matched, non‐pregnant controls (n = 12). Mice were housed individually in Promethion cages with a 12 h light–12 h dark cycle [lights on at 07.00 h, Zeitgeber (ZT)0] for behavioural analysis. Food intake between ZT10 and ZT11 was greater in pregnant than non‐pregnant mice on days 6.5–12.5 and 12.5–17.5. In mice that exhibited a peak in the last 4 h of the light phase (ZT8–ZT12), peaks were delayed by 1.6 h in the pregnant compared with the non‐pregnant group. Food intake immediately after dark‐phase onset (ZT13–ZT14) was greater in the pregnant than non‐pregnant group during days 12.5–17.5. Water intake patterns corresponded to food intake. From days 0.5–6.5 onwards, the pregnant group moved less during the dark phase, with decreased probability of being awake, in comparison to the non‐pregnant group. The onset of dark‐phase activity, peaks in activity, and wakefulness were all delayed during pregnancy. In conclusion, increased food intake during pregnancy reflects increased amplitude of eating behaviour, without longer duration. Decreases in activity also contribute to positive energy balance in pregnancy, with delays to all measured behaviours evident from mid‐pregnancy onwards. Key points: Circadian rhythms synchronise daily behaviours including eating, drinking and sleep, but how these change in pregnancy is unclear.Food intake increased, with delays in peaks of food intake behaviour late in the light phase from days 6.5 to 12.5 of pregnancy, in comparison to the non‐pregnant group.The onset of activity after lights off (dark phase) was delayed in pregnant compared with non‐pregnant mice.Activity decreased by ∼70% in the pregnant group, particularly in the dark (active) phase, with delays in peaks of wakefulness evident from days 0.5–6.5 of pregnancy onwards.These behavioural changes contribute to positive energy balance during pregnancy.Delays in circadian behaviours during mouse pregnancy were time period and pregnancy stage specific, implying different regulatory mechanisms. [ABSTRACT FROM AUTHOR]

The gut–brain axis plays a pivotal role in the finely tuned orchestration of food intake, where both homeostatic and hedonic processes collaboratively control our dietary decisions. This interplay involves the transmission of mechanical and chemical signals from the gastrointestinal tract to the appetite centers in the brain, conveying information on meal arrival, quantity, and chemical composition. These signals are processed in the brain eventually leading to the sensation of satiety and the termination of a meal. However, the regulation of food intake and appetite extends beyond the realms of pure physiological need. Hedonic mechanisms, including sensory perception (i.e., through sight, smell, and taste), habitual behaviors, and psychological factors, exert profound influences on food intake. Drawing from studies in animal models and human research, this comprehensive review summarizes the physiological mechanisms that underlie the gut–brain axis and its interplay with the reward network in the regulation of appetite and satiety. The recent advancements in neuroimaging techniques, with a focus on human studies that enable investigation of the neural mechanisms underpinning appetite regulation are discussed. Furthermore, this review explores therapeutic/pharmacological strategies that hold the potential for controlling food intake. [ABSTRACT FROM AUTHOR]

Gastrointestinal vagal afferents play an important role in communicating food related information from the gut to the brain. This information initiates vago‐vagal reflexes essential for gut functions, including gut motility and secretions. These afferents also play a role in energy homeostasis, signalling the arrival, amount and nutrient composition of a meal to the central nervous system where it is processed ultimately leading to termination of a meal. Vagal afferent responses to food related stimuli demonstrate a high degree of plasticity, responding to short term changes in nutritional demand, such as the fluctuations that occur across a 24‐hr or in response to a fast, as well as long term changes in energy demand, such as occurs during pregnancy. This plasticity is disrupted in disease states, such as obesity or chronic stress where there is hypo‐ and hypersensitivity of these afferents, respectively. Improved understanding of the plasticity of these afferents will enable identification of new treatment options for diseases associated with vagal afferent function. [ABSTRACT FROM AUTHOR]