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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] more...

Gastric vagal afferents (GVAs) sense food-related mechanical stimuli and signal to the central nervous system, to integrate control of meal termination. Pregnancy is characterized by increased maternal food intake, which is essential for normal fetal growth and to maximize progeny survival and health. However, it is unknown whether GVA function is altered during pregnancy to promote food intake. This study aimed to determine the mechanosensitivity of GVAs and food intake during early, mid-, and late stages of pregnancy in mice. Pregnant mice consumed more food compared with nonpregnant mice, notably in the light phase during mid- and late pregnancy. The increased food intake was predominantly due to light-phase increases in meal size across all stages of pregnancy. The sensitivity of GVA tension receptors to gastric distension was significantly attenuated in mid- and late pregnancy, whereas the sensitivity of GVA mucosal receptors to mucosal stroking was unchanged during pregnancy. To determine whether pregnancy-associated hormonal changes drive these adaptations, the effects of estradiol, progesterone, prolactin, and growth hormone on GVA tension receptor mechanosensitivity were determined in nonpregnant female mice. The sensitivity of GVA tension receptors to gastric distension was augmented by estradiol, attenuated by growth hormone, and unaffected by progesterone or prolactin. Together, the data indicate that the sensitivity of GVA tension receptors to tension is reduced during pregnancy, which may attenuate the perception of gastric fullness and explain increased food intake. Further, these adaptations may be driven by increases in maternal circulating growth hormone levels during pregnancy. NEW & NOTEWORTHY This study provides first evidence that gastric vagal afferent signaling is attenuated during pregnancy and inversely associated with meal size. Growth hormone attenuated mechanosensitivity of gastric vagal afferents, adding support that increases in maternal growth hormone may mediate adaptations in gastric vagal afferent signaling during pregnancy. These findings have important implications for the peripheral control of food intake during pregnancy. [ABSTRACT FROM AUTHOR] more...

Key points: The fine control of food intake is important for the maintenance of a healthy metabolic state.Gastric vagal afferents (GVAs) are involved in the peripheral regulation of food intake via signalling the degree of distension of the stomach which ultimately leads to feelings of fullness and satiety.This study provides evidence that endocannabinoids such as anandamide are capable of regulating GVA sensitivity in a concentration‐dependent biphasic manner.This biphasic effect is dependent upon interactions between the CB1, TRPV1 and GHSR receptors.These data have important implications for the peripheral control of food intake. Gastric vagal afferents (GVAs) signal to the hindbrain resulting in satiety. Endocannabinoids are endogenous ligands of cannabinoid 1 receptor (CB1) and transient receptor potential vanilloid‐1 (TRPV1) channels. The endocannabinoid anandamide (AEA) is expressed in the stomach, and its receptor CB1 is expressed in ghrelin‐positive gastric mucosal cells. Further, TRPV1, CB1 and growth hormone secretagogue receptor (ghrelin receptor, GHSR) are expressed in subpopulations of GVA neurons. This study aimed to determine the interaction between TRPV1, CB1, GHSR and endocannabinoids in the modulation of GVA signalling. An in vitro electrophysiology preparation was used to assess GVA mechanosensitivity in male C57BL/6 mice. Effects of methanandamide (mAEA; 1–100 nm), on GVA responses to stretch were determined in the absence and presence of antagonists of CB1, TRPV1, GHSR, protein kinase‐A (PKA), protein kinase‐C (PKC) and G‐protein subunits Gαi/o, or Gαq. Low doses (1–10 nm) of mAEA reduced GVA responses to 3 g stretch, whereas high doses (30–100 nm) increased the response. The inhibitory and excitatory effects of mAEA (1–100 nm) were reduced/lost in the presence of a CB1 and TRPV1 antagonist. PKA, Gαi/o or GHSR antagonists prevented the inhibitory effect of mAEA on GVA mechanosensitivity. Conversely, in the presence of a PKC or Gαq antagonist the excitatory effect of mAEA was reduced or lost, respectively. Activation of CB1, by mAEA, can activate or inhibit TRPV1 to increase or decrease GVA responses to stretch, depending on the pathway activated. These interactions could play an important role in the fine control of food intake. Key points: The fine control of food intake is important for the maintenance of a healthy metabolic state.Gastric vagal afferents (GVAs) are involved in the peripheral regulation of food intake via signalling the degree of distension of the stomach which ultimately leads to feelings of fullness and satiety.This study provides evidence that endocannabinoids such as anandamide are capable of regulating GVA sensitivity in a concentration‐dependent biphasic manner.This biphasic effect is dependent upon interactions between the CB1, TRPV1 and GHSR receptors.These data have important implications for the peripheral control of food intake. [ABSTRACT FROM AUTHOR] more...

Objective Inhibition of food intake and glucose homeostasis are both promoted when nutrients stimulate enteroendocrine cells (EEC) to release gut hormones. Several specific nutrient receptors may be located on EEC that respond to dietary sugars, amino acids and fatty acids. Bypass surgery for obesity and type II diabetes works by shunting nutrients to the distal gut, where it increases activation of nutrient receptors and mediator release, but cellular mechanisms of activation are largely unknown. We determined which nutrient receptors are expressed in which gut regions and in which cells in mouse and human, how they are associated with different types of EEC, how they are activated leading to hormone and 5-HT release. Design and results mRNA expression of 17 nutrient receptors and EEC mediators was assessed by quantitative PCR and found throughout mouse and human gut epithelium. Many species similarities emerged, in particular the dense expression of several receptors in the distal gut. Immunolabelling showed specific colocalisation of receptors with EEC mediators PYY and GLP-1 (L-cells) or 5-HT (enterochromaffin cells). We exposed isolated proximal colonic mucosa to specific nutrients, which recruited signalling pathways within specific EEC extracellular receptor-regulated kinase (p-ERK) and calmodulin kinase II (pCAMKII), as shown by subsequent immunolabelling, and activated release of these mediators. Aromatic amino acids activated both pathways in mouse, but in humans they induced only pCAMKII, which was colocalised mainly with 5-HT expression. Activation was pertussis toxin-sensitive. Fatty acid (C12) potently activated p-ERK in human in all EEC types and evoked potent release of all three mediators. Conclusions Specific nutrient receptors associate with distinct activation pathways within EEC. These may provide discrete, complementary pharmacological targets for intervention in obesity and type II diabetes. [ABSTRACT FROM AUTHOR] more...

Food intake is coordinated to cellular metabolism by clock gene expression with a master clock in the suprachiasmatic nucleus synchro-nized by light exposure. Gastric vagal afferents play a role in regulating food intake, but it is unknown whether they exhibit circadian variation in their mechanosensitivity. We aimed to determine whether gastric vagal afferents express clock genes and whether their response to mechanical stimuli oscillates throughout the light/dark cycle. Nodose ganglia were collected from 8-week-old female C57BL/6 mice every 3 h starting at lights off (1800 h) to quantify Bmall, Perl, Per2, and Nrldl mRNA by qRT-PCR. Additionally in vitro single-fiber recordings of gastric vagal mechanoreceptors were taken at all time points. Perl, Per2, Bmall, and Nrldl mRNA is expressed in the nodose ganglia and levels oscillated over a 24 h period. In mice fed ad libitum, gastric content was 3 times higher at 0000 h and 0300 h than 1200 h. The response of tension receptors to 3 g stretch was reduced by up to 70% at 2100 h, 0000 h, and 0300 h compared with 1200 h. Gastric mucosal receptor response to stroking with a 50 mg von Frey hair was 3 times greater at 1200 h and 1500 h than the response at 0000 h. Similar findings were obtained in mice fasted for 6hor maintained in darkness for 3 d before study. Therefore, these changes do not result from food intake or the light/dark cycle. Thus, gastric vagal mechanoreceptors display circadian rhythm, which may act to control food intake differentially at different times of the day. [ABSTRACT FROM AUTHOR] more...

• The circadian system plays an important role in the temporal regulation of food intake and metabolism. • This is controlled by the master clock, the superchiasmatic nucleus with receives input from the retina allowing regulation by the light:dark cycle. • The timing of food intake is another important zeitgeber playing a role in food-entrainable oscillations. • Misalignment of these oscillatory systems can have a huge impact on weight gain and metabolic disease. The circadian system plays an important role in the temporal regulation of metabolic processes as well as food intake to ensure energy efficiency. The 'master' clock is located within the superchiasmatic nucleus and receives input from the retina so that it can be entrained by the light:dark cycle. In turn, the master clock entrains other clocks in the central nervous system, including areas involved in energy homeostasis such as the arcuate nucleus, and the periphery (e.g. adipose tissue and the gastrointestinal tract). This master clock is reinforced by other zeitgebers such as the timing of food intake and activity. If these zeitgebers desynchronise, such as occurs in high fat diet-induced obesity or shift work conditions, it can lead to a misalignment of circadian clocks, disruption of metabolic processes and the development of metabolic disorders. The timing of food intake is a strong zeitgeber, particularly in the gastrointestinal tract, and therefore time restricted feeding offers potential for the treatment of diet and shift work induced metabolic disorders. This review will focus on the role of the circadian system in food intake regulation and the effect of environment factors, such as high fat diet feeding or shift work, on the temporal regulation of food intake along with the benefits of time restricted feeding. [ABSTRACT FROM AUTHOR] more...

Background: Gastric vagal afferents (GVAs) respond to mechanical stimulation, initiating satiety. These afferents exhibit diurnal fluctuations in mechanosensitivity, facilitating food intake during the dark phase in rodents. In humans, desynchrony of diurnal rhythms (eg, shift work) is associated with a higher risk of obesity. To test the hypothesis that shift work disrupts satiety signaling, the effect of a rotating light cycles on diurnal rhythms in GVA mechanosensitivity in lean and high‐fat diet (HDF)‐induced obese mice was determined. Methods: Male C57BL/6 mice were fed standard laboratory diet (SLD) or HFD for 12 weeks. After 4 weeks, mice were randomly allocated to a normal light (NL; 12 hour light: 12 hour dark; lights on at zeitgeber time [ZT] 0) or rotating light (RL; 3‐day NL cycle, 4‐day reversed light cycle [lights on: ZT12] repeated) cycle for 8 weeks. At week 12, eight mice from each group were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 hour intervals starting at ZT0. Key Results: SLD‐RL and HFD‐RL gained more weight compared to SLD‐NL and HFD‐NL mice, respectively. Gonadal fat pad mass was higher in SLD‐RL compared to SLD‐NL mice. In SLD‐NL mice, tension and mucosal receptor mechanosensitivity exhibited diurnal rhythms with a peak at ZT9. These rhythms were lost in SLD‐RL, HFD‐NL, and HFD‐RL mice and associated with dampened diurnal rhythms in food intake. Conclusions & Inferences: GVA diurnal rhythms are susceptible to disturbances in the light cycle and/or the obese state. This may underpin the observed changes in feeding behavior. [ABSTRACT FROM AUTHOR] more...

Small intestinal satiation pathways involve nutrient-induced stimulation of chemoreceptors leading to release of satiety hormones from intestinal enteroendocrine cells (ECCs). Whether adaptations in these pathways contribute to increased maternal food intake during pregnancy is unknown. To determine the expression of intestinal nutrient-sensors and satiety hormone transcripts and proteins across pregnancy in mice. Female C57BL/6J mice (10–12 weeks old) were randomized to mating and then tissue collection at early- (6.5 d), mid- (12.5 d) or late-pregnancy (17.5 d), or to an unmated age matched control group. Relative transcript expression of intestinal fatty acid, peptide and amino acid and carbohydrate chemoreceptors, as well as gut hormones was determined across pregnancy. The density of G-protein coupled receptor 93 (GPR93), free fatty acid receptor (FFAR) 4, cholecystokinin (CCK) and glucagon-like peptide1 (GLP-1) immunopositive cells was then compared between non-pregnant and late-pregnant mice. Duodenal GPR93 expression was lower in late pregnant than non-pregnant mice (P < 0.05). Ileal FFAR1 expression was higher at mid- than at early- or late-pregnancy. Ileal FFAR2 expression was higher at mid-pregnancy than in early pregnancy. Although FFAR4 expression was consistently lower in late-pregnant than non-pregnant mice (P < 0.001), the density of FFAR4 immunopositive cells was higher in the jejunum of late-pregnant than non-pregnant mice. A subset of protein and fatty acid chemoreceptor transcripts undergo region-specific change during murine pregnancy, which could augment hormone release and contribute to increased food intake. Further investigations are needed to determine the functional relevance of these changes. • Adaptations in intestinal chemoreceptors and hormones during pregnancy is unknown. • Duodenal GPR93 and intestinal FFAR4 expression was lower in late-pregnant mice. • FFAR4 positive cells were greater in the jejunum of late- vs. non-pregnant mice. • Gut hormone (CCK & GLP-1) expression and cell density was unchanged in pregnancy. [ABSTRACT FROM AUTHOR] more...

Neuropeptide W (NPW) is secreted from gastrin (G) cells in the stomach in response to food intake. The mechanisms underlying food intake-induced regulation of gastric NPW is largely unknown. We hypothesized that specific macronutrients were responsible for food-induced NPW secretion. We evaluated the acute effects of fat, carbohydrate and protein on plasma NPW concentrations in humans and mice. The effect of different nutrients on expression of NPW in the antral stomach was also determined in mice. Primary cell cultures of mouse gastric antral mucosal cells were used to investigate the signaling pathway of NPW expression. Plasma NPW concentrations did not change after nutrient ingestion in either humans or mice. NPW mRNA expression and the number of NPW positive cells in the mouse antrum were increased in mice gavage fed with protein or glucose, but not lipid. In primary antral mucosal cell culture, NPW mRNA expression was stimulated by l -phenylalanine, but not glucose. Calcium-sensing receptor (CaSR) positive cells were largely co-localized with NPW in mouse gastric antral mucosal cells, and NPW mRNA expression was inhibited by a selective antagonist of CaSR NPS2143. However, the l -phenylalanine-induced increase in NPW expression was not affected by NPS2143. In conclusion, these studies indicated an inconsistency between plasma and gastric NPW expression in response to nutrient ingestion, suggesting food induced gastric NPW expression may play a more important role locally. Moreover, glucose and especially protein are potent regulators of gastric NPW, via distinct mechanisms. [ABSTRACT FROM AUTHOR] more...