Adaptations in Gastrointestinal Nutrient Absorption and its Determinants During Pregnancy in Monogastric Mammals: A Scoping Review.

CONTEXT: Pregnancy increases nutrient demand, but how nutrient uptake and its determinants adapt to facilitate this is unclear. OBJECTIVE: This review aimed to identify and characterize evidence and evidence gaps regarding changes in gastrointestinal nutrient absorption and its determinants during pregnancy in monogastric mammals. DATA SOURCES: A scoping review of peer-reviewed sources was conducted across PubMed, Scopus, Web of Science, Embase, and ProQuest (theses and dissertations) databases. DATA EXTRACTION: Data extracted included species, pregnancy stages and outcomes. Where sufficient data for a given outcome was available, relative values were summarized graphically or in tables, to allow comparison across pregnancy stages and/or small intestine regions. Searches identified 26 855 sources, of which only 159 were eligible. Mechanistic studies were largely restricted to rodents, and most compared non- and late-pregnant groups, with fewer studies including early- or mid-pregnant groups. DATA ANALYSIS: During pregnancy, there is some evidence for greater capacity for glucose uptake but unchanged amino acid uptake, and good evidence for increased uptake of calcium, iron, and zinc, and slower gastrointestinal passage of nutrients. The available evidence indicates that acute glucose uptake, gastric emptying, and the activities of sucrase, maltase, and lactase do not change during pregnancy. Gaps in the knowledge include the effects of pregnancy on uptake of specific amino acids, lipids, and most minerals and vitamins. CONCLUSION: The results indicate that the gastrointestinal tract adapts during pregnancy to facilitate increased nutrient absorption. Additional data is required in order to assess the underlying mechanisms for and impacts on the absorption of many nutrients, as well as to determine the timing of these adaptations.

Circadian patterns of behaviour change during pregnancy in mice.

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.

Effect of pregnancy on the expression of nutrient-sensors and satiety hormones in mice.

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.

Plasticity of gastrointestinal vagal afferents in terms of feeding-related physiology and pathophysiology.

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.

Advancing translational research for colorectal immuno-oncology.

Colorectal cancer (CRC) is a common and deadly disease. Unfortunately, immune checkpoint inhibitors (ICIs) fail to elicit effective anti-tumour responses in the vast majority of CRC patients. Patients that are most likely to respond are those with DNA mismatch repair deficient (dMMR) and microsatellite instability (MSI) disease. However, reliable predictors of ICI response are lacking, even within the dMMR/MSI subtype. This, together with identification of novel mechanisms to increase response rates and prevent resistance, are ongoing and vitally important unmet needs. To address the current challenges with translation of early research findings into effective therapeutic strategies, this review summarises the present state of preclinical testing used to inform the development of immuno-regulatory treatment strategies for CRC. The shortfalls and advantages of commonly utilised mouse models of CRC, including chemically induced, transplant and transgenic approaches are highlighted. Appropriate use of existing models, incorporation of patient-derived data and development of cutting-edge models that recapitulate important features of human disease will be key to accelerating clinically relevant research in this area.

The association between diet quality, plant-based diets, systemic inflammation, and mortality risk: findings from NHANES.

PURPOSE: To our knowledge, no studies have examined the association of diet quality and plant-based diets (PBD) with inflammatory-related mortality in obesity. Therefore, this study aimed to determine the joint associations of Healthy Eating Index-2015 (HEI-2015), plant-based dietary index (PDI), healthy PDI (hPDI), unhealthy PDI (uPDI), pro-vegetarian dietary index (PVD), and systemic inflammation with all-cause, cardiovascular disease (CVD), and cancer mortality risks by obesity status. METHODS: Participants from NHANES were included in cross-sectional (N = 27,915, cycle 1999-2010, 2015-2018) and longitudinal analysis (N = 11,939, cycle 1999-2008). HEI-2015, PDI, hPDI, uPDI, and PVD were constructed based on the 24-h recall dietary interview. The grade of inflammation (low, moderate, and high) was determined based on C-reactive protein (CRP) values and multivariable ordinal logistic regression was used to determine the association. Cox proportional hazard models were used to determine the joint associations of diet and inflammation with mortality. RESULTS: In the fully adjusted model, HEI-2015 (ORT3vsT1 = 0.76, 95% CI 0.69-0.84; p-trend = < 0.001), PDI (ORT3vsT1 = 0.83, 95% CI 0.75-0.91; p trend = < 0.001), hPDI (ORT3vsT1 = 0.79, 95% CI 0.71-0.88; p trend = < 0.001), and PVD (ORT3vsT1 = 0.85, 95% CI 0.75-0.97; p trend = 0.02) were associated with lower systemic inflammation. In contrast, uPDI was associated with higher systemic inflammation (ORT3vsT1 = 1.18, 95% CI 1.06-1.31; p-trend = 0.03). Severe inflammation was associated with a 25% increase in all-cause mortality (ORT3vsT1 = 1.25, 95% CI 1.03-1.53, p trend = 0.02). No association was found between PDI, hPDI, uPDI, and PVD with mortality. The joint association, between HEI-2015, levels of systemic inflammation, and all-cause, CVD and cancer mortality, was not significant. However, a greater reduction in mortality risk with an increase in HEI-2015 scores was observed in individuals with low and moderate inflammation, especially those with obesity. CONCLUSION: Higher scores of HEI-2015 and increased intake of a healthy plant-based diet were associated with lower inflammation, while an unhealthy plant-based diet was associated with higher inflammation. A greater adherence to the 2015 dietary guidelines may reduce the risk of mortality associated with inflammation and may also benefit individuals with obesity who had low and moderate inflammation.

Active glucose transport varies by small intestinal region and oestrous cycle stage in mice.

NEW FINDINGS: What is the central question of this study? Body mass and food intake change during the female ovarian cycle: does glucose transport by the small intestine also vary? What is the main finding and its importance? We have optimised Ussing chamber methodology to measure region-specific active glucose transport in the small intestine of adult C57BL/6 mice. Our study provides the first evidence that jejunal active glucose transport changes during the oestrous cycle in mice, and is higher at pro-oestrus than oestrus. These results demonstrate adaptation in active glucose uptake, concurrent with previously reported changes in food intake. ABSTRACT: Food intake changes across the ovarian cycle in rodents and humans, with a nadir during the pre-ovulatory phase and a peak during the luteal phase. However, it is unknown whether the rate of intestinal glucose absorption also changes. We therefore mounted small intestinal sections from C57BL/6 female mice (8-9 weeks old) in Ussing chambers and measured active ex vivo glucose transport via the change in short-circuit current (∆Isc ) induced by glucose. Tissue viability was confirmed by a positive ∆Isc response to 100 µM carbachol following each experiment. Active glucose transport, assessed after addition of 5, 10, 25 or 45 mM d-glucose to the mucosal chamber, was highest at 45 mM glucose in the distal jejunum compared to duodenum and ileum (P < 0.01). Incubation with the sodium-glucose cotransporter 1 (SGLT1) inhibitor phlorizin reduced active glucose transport in a dose-dependent manner in all regions (P < 0.01). Active glucose uptake induced by addition of 45 mM glucose to the mucosal chamber in the absence or presence of phlorizin was assessed in jejunum at each oestrous cycle stage (n = 9-10 mice per stage). Overall, active glucose uptake was lower at oestrus compared to pro-oestrus (P = 0.025). This study establishes an ex vivo method to measure region-specific glucose transport in the mouse small intestine. Our results provide the first direct evidence that SGLT1-mediated glucose transport in the jejunum changes across the ovarian cycle. The mechanisms underlying these adaptations in nutrient absorption remain to be elucidated.

Association of dietary and nutrient patterns with systemic inflammation in community dwelling adults.

Purpose: Evidence investigating associations between dietary and nutrient patterns and inflammatory biomarkers is inconsistent and scarce. Therefore, we aimed to determine the association of dietary and nutrient patterns with inflammation. Methods: Overall, 1,792 participants from the North-West Adelaide Health Study were included in this cross-sectional study. We derived dietary and nutrient patterns from food frequency questionnaire data using principal component analysis. Multivariable ordinal logistic regression determined the association between dietary and nutrient patterns and the grade of inflammation (normal, moderate, and severe) based on C-reactive protein (CRP) values. Subgroup analyses were stratified by gender, obesity and metabolic health status. Results: In the fully adjusted model, a plant-sourced nutrient pattern (NP) was strongly associated with a lower grade of inflammation in men (ORQ5vsQ1 = 0.59, 95% CI: 0.38-0.93, p-trend = 0.08), obesity (ORQ5vsQ1 = 0.43; 95% CI: 0.24-0.77, p-trend = 0.03) and metabolically unhealthy obesity (ORQ5vsQ1 = 0.24; 95% CI: 0.11-0.52, p-trend = 0.01). A mixed NP was positively associated with higher grade of inflammation (ORQ5vsQ1 = 1.35; 95% CI: 0.99-1.84, p-trend = 0.03) in all participants. A prudent dietary pattern was inversely associated with a lower grade of inflammation (ORQ5vsQ1 = 0.72, 95% CI: 0.52-1.01, p-trend = 0.14). In contrast, a western dietary pattern and animal-sourced NP were associated with a higher grade of inflammation in the all participants although BMI attenuated the magnitude of association (ORQ5vsQ1 = 0.83, 95% CI: 0.55-1.25; and ORQ5vsQ1 = 0.94, 95% CI: 0.63-1.39, respectively) in the fully adjusted model. Conclusion: A plant-sourced NP was independently associated with lower inflammation. The association was stronger in men, and those classified as obese and metabolically unhealthy obese. Increasing consumption of plant-based foods may mitigate obesity-induced inflammation and its consequences.

Intermittent fasting activates markers of autophagy in mouse liver, but not muscle from mouse or humans.

OBJECTIVES: Intermittent fasting (IF) activates autophagy in cardiac muscle and pancreatic islets. We examined the effect of IF on markers of autophagy in liver and skeletal muscle in mice and in humans. METHODS: Ten-wk-old C57 BL/6 J male mice were ad libitum (AL) fed a high-fat diet (HFD) or chow diet for 8 wk, before randomization to AL or IF (24-h fast, 3 non-consecutive days per week) for 8 wk (8-16 per group). Tissue was collected in the fed or 22-h fasted state. Fifty women (51 ± 2 y, 31.8 ± 4.3 kg/m2) were randomly assigned to one of two IF protocols (24-hfast, 3 non-consecutive days per week) and fed at 70% (IF70) or 100% (IF100) of energy requirements for 8 wk. Vastus lateralis muscle was collected at 0800 after 12- and 24-h fasts. Microtubule-associated protein light chain 1 (Map1 lc3 b), Beclin1 (Becn1), Sequestosome 1 (Sqstm1/p62), and Lysosomal associated membrane protein 2 (Lamp2) were assessed by quantitative polymerase chain reaction and LC3, BECLIN1 and LAMP1 protein content by immunoblotting. RESULTS: Fasting increased hepatic LC3 I protein and Map1 lc3 b mRNA levels in IF mice fed chow or HFD. LAMP1 protein and Beclin1 mRNA levels in liver were also increased by fasting, but only in chow-fed mice. IF did not activate markers of autophagy in mouse muscle. In humans, a 24-h fast increased SQSTM1. BECLIN1, SQSTM1 and LAMP2 mRNA levels were decreased in IF70 after a 12-h overnight fast . CONCLUSION: Markers of autophagy in liver, but not in muscle, were elevated in response to IF in mice. In humans, autophagy markers in muscle were reduced, likely in response to weight loss.

Altered Vagal Signaling and Its Pathophysiological Roles in Functional Dyspepsia.

The vagus nerve is crucial in the bidirectional communication between the gut and the brain. It is involved in the modulation of a variety of gut and brain functions. Human studies indicate that the descending vagal signaling from the brain is impaired in functional dyspepsia. Growing evidence indicate that the vagal signaling from gut to brain may also be altered, due to the alteration of a variety of gut signals identified in this disorder. The pathophysiological roles of vagal signaling in functional dyspepsia is still largely unknown, although some studies suggested it may contribute to reduced food intake and gastric motility, increased psychological disorders and pain sensation, nausea and vomiting. Understanding the alteration in vagal signaling and its pathophysiological roles in functional dyspepsia may provide information for new potential therapeutic treatments of this disorder. In this review, we summarize and speculate possible alterations in vagal gut-to-brain and brain-to-gut signaling and the potential pathophysiological roles in functional dyspepsia.

Adaptations in gastrointestinal nutrient absorption and its determinants during pregnancy in monogastric mammals: a scoping review protocol.

OBJECTIVE: The aim of this review is to characterize the current state of literature and knowledge regarding adaptations of gastrointestinal nutrient absorption, and the determinants of this absorption during pregnancy in monogastric mammals. INTRODUCTION: Energy demands increase significantly during pregnancy due to the metabolic demands associated with placental and fetal growth, and the deposition of fat stores that support postnatal lactation. Previous studies have examined anatomical changes within the small intestine, but have focused on specific pregnancy stages or specific regions of the small intestine. Importantly, little is known about changes in nutrient absorption during pregnancy, and the underlying mechanisms that lead to these changes. An understanding of these adaptations will inform research to improve pregnancy outcomes for both mothers and newborns in the future. INCLUSION CRITERIA: This review will include primary literature that describes gastrointestinal nutrient absorption and/or its determinants during pregnancy in monogastric mammals, including humans and rodents. Only data for normal pregnancies will be included, and models of pathology and illness will be excluded. Studies must include comparisons between pregnant animals at known stages of pregnancy, and non-pregnant controls, or compare animals at different stages of pregnancy. METHODS: The following databases will be searched for literature on this topic: PubMed, Scopus, Web of Science, Embase, MEDLINE, and ProQuest Dissertations and Theses. Evidence screening and selection will be carried out independently by two reviewers, and conflicts will be resolved through discussion with additional members of the review team. Data will be extracted and presented in tables and/or figures, together with a narrative summary.

The secretion of total and acyl ghrelin from the mouse gastric mucosa: Role of nutrients and the lipid chemosensors FFAR4 and CD36.

AIMS: This study investigated the nutrient-mediated modulation of total ghrelin (TG) and acyl ghrelin (AG) secretion from the mouse gastric mucosa, and the role of long-chain fatty acid chemosensors, FFAR4 and CD36, in lipid-mediated modulation of TG and AG release. METHODS: Ex-vivo experiments were conducted using mouse gastric mucosa to examine the effects of nutrients (D-glucose, L-phenylalanine, peptone (mixture of oligopeptides & single amino acids), D-mannitol, α-linolenic acid and fat emulsion (intralipid)) on TG and AG secretion. Additionally, inhibition of FFAR4 and CD36 on α-linolenic acid and intralipid-mediated regulation of TG and AG secretion was assessed. RESULTS: TG and AG secretion were unaffected by glucose and D-mannitol. Peptone stimulated the release of TG and AG. In contrast, L-phenylalanine reduced AG secretion only. Intralipid reduced TG secretion and stimulated AG secretion, and α-linolenic acid reduced AG release, without affecting TG mobilisation. Modulation of ghrelin secretion by lipids occurred in an FFAR4 and CD36-independent manner. CONCLUSION: Ghrelin secretion is modulated in a nutrient-specific manner by proteins and lipids, with TG and AG displaying independent responses to the same stimuli. In addition, FFAR4 and CD36 do not participate in modulation of TG and AG secretion by α-linolenic acid and intralipid.

Maternal adaptations to food intake across pregnancy: Central and peripheral mechanisms.

A sufficient and balanced maternal diet is critical to meet the nutritional demands of the developing fetus and to facilitate deposition of fat reserves for lactation. Multiple adaptations occur to meet these energy requirements, including reductions in energy expenditure and increases in maternal food intake. The central nervous system plays a vital role in the regulation of food intake and energy homeostasis and responds to multiple metabolic and nutrient cues, including those arising from the gastrointestinal tract. This review describes the nutrient requirements of pregnancy and the impact of over- and undernutrition on the risk of pregnancy complications and adult disease in progeny. The central and peripheral regulation of food intake is then discussed, with particular emphasis on the adaptations that occur during pregnancy and the mechanisms that drive these changes, including the possible role of the pregnancy-associated hormones progesterone, estrogen, prolactin, and growth hormone. We identify the need for deeper mechanistic understanding of maternal adaptations, in particular, changes in gut-brain axis satiety signaling. Improved understanding of food intake regulation during pregnancy will provide a basis to inform strategies that prevent maternal under- or overnutrition, improve fetal health, and reduce the long-term health and economic burden for mothers and offspring.

Association between Dietary Inflammatory Index, Dietary Patterns, Plant-Based Dietary Index and the Risk of Obesity.

Evidence on the association between various dietary constructs and obesity risk is limited. This study aims to investigate the longitudinal relationship between different diet indices and dietary patterns with the risk of obesity. Non-obese participants (n = 787) in the North West Adelaide Health Study were followed from 2010 to 2015. The dietary inflammatory index (DII®), plant-based dietary index (PDI) and factor-derived dietary pattern scores were computed based on food frequency questionnaire data. We found the incidence of obesity was 7.62% at the 5-year follow up. In the adjusted model, results from multivariable log-binomial logistic regression showed that a prudent dietary pattern (RRQ5 vs. Q1 = 0.38; 95% CI: 0.15-0.96), healthy PDI (RR = 0.31; 95% CI: 0.12-0.77) and overall PDI (RR = 0.56; 95% CI: 0.23-1.33) were inversely associated with obesity risk. Conversely, the DII (RR = 1.59; 95% CI: 0.72-3.50), a Western dietary pattern (RR = 2.16; 95% CI: 0.76-6.08) and unhealthy PDI (RR = 1.94; 95% CI: 0.81-4.66) were associated with increased risk of obesity. Based on the cubic spline analysis, the association between an unhealthy PDI or diet quality with the risk of obesity was non-linear. In conclusion, an anti-inflammatory diet, healthy diet or consumption of healthy plant-based foods were all associated with a lower risk of developing obesity.

Role of Indices Incorporating Power, Force and Time in AF Ablation: A Systematic Review of Literature.

INTRODUCTION: Successful pulmonary vein isolation (PVI) for atrial fibrillation (AF) depends on the formation of durable transmural lesions. Recently, novel indices have emerged to guide lesion delivery. The aim of the systematic review of literature was to determine AF recurrence following ablation guided by indices incorporating force, power and time, and compare acute procedural outcomes and 12-month AF recurrence with ablation guided by contact force (CF) guided only. METHODS: PubMed, EMBASE, and Web of Science Core Collection databases were searched on 27 January 2020 using the keywords; catheter ablation, ablation index (AI), lesion size index (LSI), contact force, atrial fibrillation. RESULTS: After exclusions, seven studies were included in the analysis. AI-guided catheter ablation was associated with a 91% (n=5, 0.91 95% CI; 0.88-0.93) and 80% (n=5, 0.80, 95% CI; 0.77-0.84) freedom from AF at 12 months with and without the use of anti-arhythmic drugs respectively. As compared to CF guided ablation, AI-guided catheter ablation was associated with a 49% increase in successful first pass isolation (n=3; RR: 1.49, 95% CI; 1.38, 1.61), a 50% decrease in number of acute reconnections (n=4; RR: 0.50, 95% CI; 0.39-0.65) and a 22% (n=4, RR: 1.22, 95% CI; 1.10-1.35) increase in AF freedom without anti-arrhythmic drugs at 12 months. CONCLUSIONS: Radiofrequency ablation guided by AI was associated with higher successful first pass isolation and lower rates of acute reconnection which translates to greater freedom from AF at 12 months [CRD42019131469].

Deletion of Rptor in Preosteoblasts Reveals a Role for the Mammalian Target of Rapamycin Complex 1 (mTORC1) Complex in Dietary-Induced Changes to Bone Mass and Glucose Homeostasis in Female Mice.

The mammalian target of rapamycin complex 1 (mTORC1) complex is the major nutrient sensor in mammalian cells that responds to amino acids, energy levels, growth factors, and hormones, such as insulin, to control anabolic and catabolic processes. We have recently shown that suppression of the mTORC1 complex in bone-forming osteoblasts (OBs) improved glucose handling in male mice fed a normal or obesogenic diet. Mechanistically, this occurs, at least in part, by increasing OB insulin sensitivity leading to upregulation of glucose uptake and glycolysis. Given previously reported sex-dependent differences observed upon antagonism of mTORC1 signaling, we investigated the metabolic and skeletal effects of genetic inactivation of preosteoblastic-mTORC1 in female mice. Eight-week-old control diet (CD)-fed Rptor ob -/- mice had a low bone mass with a significant reduction in trabecular bone volume and trabecular number, reduced cortical bone thickness, and increased marrow adiposity. Despite no changes in body composition, CD-fed Rptor ob -/- mice exhibited significant lower fasting insulin and glucose levels and increased insulin sensitivity. Upon high-fat diet (HFD) feeding, Rptor ob -/- mice were resistant to a diet-induced increase in whole-body and total fat mass and protected from the development of diet-induced insulin resistance. Notably, although 12 weeks of HFD increased marrow adiposity, with minimal changes in both trabecular and cortical bone in the female control mice, marrow adiposity was significantly reduced in HFD-fed Rptor ob -/- compared to both HFD-fed control and CD-fed Rptor ob -/- mice. Collectively, our results demonstrate that mTORC1 function in preosteoblasts is crucial for skeletal development and skeletal regulation of glucose homeostasis in both male and female mice. Importantly, loss of mTORC1 function in OBs results in metabolic and physiological adaptations that mirror a caloric restriction phenotype (under CD) and protects against HFD-induced obesity, associated insulin resistance, and marrow adiposity expansion. These results highlight the critical contribution of the skeleton in the regulation of whole-body energy homeostasis. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Gastrointestinal Vagal Afferents and Food Intake: Relevance of Circadian Rhythms.

Gastrointestinal vagal afferents (VAs) play an important role in food intake regulation, providing the brain with information on the amount and nutrient composition of a meal. This is processed, eventually leading to meal termination. The response of gastric VAs, to food-related stimuli, is under circadian control and fluctuates depending on the time of day. These rhythms are highly correlated with meal size, with a nadir in VA sensitivity and increase in meal size during the dark phase and a peak in sensitivity and decrease in meal size during the light phase in mice. These rhythms are disrupted in diet-induced obesity and simulated shift work conditions and associated with disrupted food intake patterns. In diet-induced obesity the dampened responses during the light phase are not simply reversed by reverting back to a normal diet. However, time restricted feeding prevents loss of diurnal rhythms in VA signalling in high fat diet-fed mice and, therefore, provides a potential strategy to reset diurnal rhythms in VA signalling to a pre-obese phenotype. This review discusses the role of the circadian system in the regulation of gastrointestinal VA signals and the impact of factors, such as diet-induced obesity and shift work, on these rhythms.

The mTORC1 complex in pre-osteoblasts regulates whole-body energy metabolism independently of osteocalcin.

Overnutrition causes hyperactivation of mTORC1-dependent negative feedback loops leading to the downregulation of insulin signaling and development of insulin resistance. In osteoblasts (OBs), insulin signaling plays a crucial role in the control of systemic glucose homeostasis. We utilized mice with conditional deletion of Rptor to investigate how the loss of mTORC1 function in OB affects glucose metabolism under normal and overnutrition dietary states. Compared to the controls, chow-fed Rptorob-/- mice had substantially less fat mass and exhibited adipocyte hyperplasia. Remarkably, upon feeding with high-fat diet, mice with pre- and post-natal deletion of Rptor in OBs were protected from diet-induced obesity and exhibited improved glucose metabolism with lower fasting glucose and insulin levels, increased glucose tolerance and insulin sensitivity. This leanness and resistance to weight gain was not attributable to changes in food intake, physical activity or lipid absorption but instead was due to increased energy expenditure and greater whole-body substrate flexibility. RNA-seq revealed an increase in glycolysis and skeletal insulin signaling pathways, which correlated with the potentiation of insulin signaling and increased insulin-dependent glucose uptake in Rptor-knockout osteoblasts. Collectively, these findings point to a critical role for the mTORC1 complex in the skeletal regulation of whole-body glucose metabolism and the skeletal development of insulin resistance.