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Heat-stressed dairy cows on pasture will compete for resources that aid cooling, but it is not known how heat stress affects the competition for water by indoor-housed cows. The aim of this observational study was to evaluate how heat stress affects the behavior of indoor-housed cows at the drinker at both group and cow levels. For 3 wk after calving, cows were housed in a dynamic group of 20 animals in a pen with 12 electronic feed bins, 2 electronic water bins, and 24 freestalls. A total of 69 lactating Holstein dairy cows were enrolled over the 59-d study. The electronic water bins recorded time spent at the drinker, frequency of visits, water intake, and competitive events for 24 h/d. Competitive events were quantified using the number of replacements (recorded when there was a ≤29-s interval between 2 cows sequentially visiting the same drinker). The number of replacements a cow was involved in was used to determine her level of competitive success at the drinker (low, medium, high). The temperature–humidity index (THI) was recorded by the local weather station, and moving averages for daily maximum THI over a 3-d period were calculated. For the analysis of time spent at the drinker, frequency of visits, and water intake, the measures from all cows were averaged to create 1 observation per day, and the number of replacements at the drinker was summed. A linear regression was performed to determine the relationship between THI and group-level drinking behavior. At the cow level, a repeated measures mixed model, with fixed effects of level of competitive success, milk yield, and 3-d maximum THI and a first-order autoregressive covariance structure, was used to determine how increasing THI affects the drinking behavior of individual cows based on their level of competitive success. Feed intake was included as a fixed effect in the water intake model. We found that, with increasing THI, cows drank more water, spent more time at the drinker, made more visits to the drinker, and engaged in more competitive events at the drinker. In exploratory analysis, we found that cows with low competitive success at the drinker shifted their drinking behavior to avoid the drinker at the hottest and most competitive time of day. These results indicate that behavior can be used to indicate when cows feel hot. These measures may be of practical value in deciding when to provide cooling, especially for farms where attendance at the drinker can be monitored electronically.

The objective of this study was to determine whether data from an electronic drinking system that tracks individual animal attendance with ear tag transponders could be used to detect social competition between dairy cows at the drinker. Specifically, we sought to identify the interval between one cow leaving the drinker and another cow taking her place that most accurately identified competitive replacements (when physical contact initiated by one cow causes the other to entirely remove her head from the drinker and the initiator subsequently places her head in the same drinker). The optimal interval to accurately identify replacements at the drinker was determined using a receiver operating characteristic curve and by evaluating the sensitivity (Se), specificity (Sp), and confusion matrix values (true positives, true negatives, false positives, false negatives) of different thresholds identified by 3 metrics: the Youden index, the point closest to (0,1) on the curve, and the point where Se roughly equals Sp. Lactating Holstein dairy cows (n = 20) were monitored for 4 consecutive 24-h periods by video recording and with an electronic drinking system. Two periods were used to identify the optimal interval (the baseline set), and the other 2 periods were used to validate the interval (the validation set). The occurrence of a replacement identified by video was paired with the interval between drinking events of 2 cows at the same electronic drinker to identify the interval that best predicted replacement events. Based on the low prevalence of replacement events compared with nonreplacement events, the interval with the lowest number of false positives was considered optimal. Of the 3 potential metrics, the point on the receiver operating characteristic curve where Se and Sp were roughly equal yielded the fewest false positives. The optimal interval to identify replacements at the drinker was ≤29 s, with 82% Se and 83% Sp in the baseline set. This interval was found to have 85% Se and 89% Sp when applied to the validation set. These results indicate that social competition between dairy cows at the drinker can be accurately measured with an electronic drinking system.

Proper development of the O

Glucose homeostasis is partly controlled by the energy sensor mechanistic target of rapamycin (mTOR) in the muscle and liver. However, whether mTOR in the small intestine affects glucose homeostasis in vivo remains unknown. Here, we first report that delivery of rapamycin or an adenovirus encoding the dominant negative acting mTOR-mutated protein into the upper small intestine is sufficient to inhibit small intestinal mTOR signaling and lower glucose production in rodents with high fat diet-induced insulin resistance. Second, we found that molecular activation of small intestinal mTOR blunts the glucose-lowering effect of the oral anti-diabetic agent metformin, while inhibiting small intestinal mTOR alone lowers plasma glucose levels by inhibiting glucose production in rodents with diabetes as well. Thus, these findings illustrate that inhibiting upper small intestinal mTOR is sufficient and necessary to lower glucose production and enhance glucose homeostasis, and thereby unveil a previously unappreciated glucose-lowering effect of small intestinal mTOR., The mechanistic target of rapamycin (TOR) functions as an energy sensor and contributes to the control of glucose homeostasis. Here, the authors show that mTOR in the upper small intestine regulates hepatic glucose production and is required for the glucose lowering effect of metformin.

The interaction between developmental plasticity and the capacity for reversible acclimation (phenotypic flexibility) is poorly understood, particularly in organisms exposed to fluctuating environments. We used an amphibious killifish (Kryptolebias marmoratus) to test the hypotheses that organisms reared in fluctuating environments (i) will make no developmental changes to suit any one environment because fixing traits to suit one environment could be maladaptive for another, and (ii) will be highly phenotypically flexible as adults because their early life experiences predict high environmental variability in the future. We reared fish under constant (water) or fluctuating (water-air) environments until adulthood and assessed a suite of traits along the oxygen (O2) cascade (e.g., neuroepithelial cell density and size, cutaneous capillarity, gill morphology, ventricle size, red muscle morphometrics, terrestrial locomotor performance). To evaluate the capacity for phenotypic flexibility, a subset of adult fish from each rearing condition were then air-exposed for 14 days before the same traits were measured. In support of the developmental plasticity hypothesis, traits involved with O2 sensing and uptake were largely unaffected by water-air fluctuations during early life, but we found marked developmental changes in traits related to O2 transport, utilization, and locomotor performance. In contrast, we found no evidence supporting the phenotypic flexibility hypothesis. Adult fish from both rearing conditions exhibited the same degree of phenotypic flexibility in various O2 sensing- and uptake-related traits. In other cases, water-air fluctuations attenuated adult phenotypic flexibility despite the fact that phenotypic flexibility is hypothesized to be favoured when environments fluctuate. Overall, we conclude that exposure to environmental fluctuations during development in K. marmoratus can dramatically alter the constitutive adult phenotype, as well as diminish the scope for phenotypic flexibility in later life.

High protein feeding improves glucose homeostasis in rodents and humans with diabetes, but the mechanisms that underlie this improvement remain elusive. Here we show that acute administration of casein hydrolysate directly into the upper small intestine increases glucose tolerance and inhibits glucose production in rats, independently of changes in plasma amino acids, insulin levels, and food intake. Inhibition of upper small intestinal peptide transporter 1 (PepT1), the primary oligopeptide transporter in the small intestine, reverses the preabsorptive ability of upper small intestinal casein infusion to increase glucose tolerance and suppress glucose production. The glucoregulatory role of PepT1 in the upper small intestine of healthy rats is further demonstrated by glucose homeostasis disruption following high protein feeding when PepT1 is inhibited. PepT1-mediated protein-sensing mechanisms also improve glucose homeostasis in models of early-onset insulin resistance and obesity. We demonstrate that preabsorptive upper small intestinal protein-sensing mechanisms mediated by PepT1 have beneficial effects on whole-body glucose homeostasis., High protein diets are known to improve metabolic parameters including adiposity and glucose homeostasis. Here the authors demonstrate that preabsorptive upper small intestinal protein-sensing mechanisms mediated by peptide transporter 1 improve glucose homeostasis by inhibiting hepatic glucose production.

Mitochondria undergo dynamic changes to maintain function in eukaryotic cells. Insulin action in parallel regulates glucose homeostasis, but whether specific changes in mitochondrial dynamics alter insulin action and glucose homeostasis remains elusive. Here, we report that high-fat feeding in rodents incurred adaptive dynamic changes in mitochondria through an increase in mitochondrial fission in parallel to an activation of dynamin-related protein 1 (Drp1) in the dorsal vagal complex (DVC) of the brain. Direct inhibition of Drp1 negated high-fat-feeding-induced mitochondrial fission, endoplasmic reticulum (ER) stress, and insulin resistance in the DVC and subsequently restored hepatic glucose production regulation. Conversely, molecular activation of DVC Drp1 in healthy rodents was sufficient to induce DVC mitochondrial fission, ER stress, and insulin resistance. Together, these data illustrate that Drp1-dependent mitochondrial fission changes in the DVC regulate insulin action and suggest that targeting the Drp1-mitochondrial-dependent pathway in the brain may have therapeutic potential in insulin resistance.

The ability to tolerate environmental change may decline as fishes age. We tested the hypothesis that ageing influences the scope for phenotypic flexibility in the mangrove rivulus (Kryptolebias marmoratus), an amphibious fish that transitions between two vastly different environments, water and land. We found that older fish (4-6 years old) exhibited marked signs of ageing; older fish were reproductively senescent, had reduced fin regenerative capacity and body condition, and exhibited atrophy of both oxidative and glycolytic muscle fibers relative to younger adult fish (1-2 years old). However, age did not affect routine O

Mechanical loading is an essential stimulus for skeletal tissues. Osteocytes are primarily responsible for sensing mechanical stimuli in bone and for orchestrating subsequent responses. This is critical for maintaining homeostasis, and responding to injury/disease. The osteocyte mechanotransduction pathway, and the downstream effects it mediates, is highly complex. In vivo models have proved invaluable in understanding this process. This review summarizes the commonly used models, as well as more recently developed ones, and describes how they are used to address emerging questions in the field. Minimally invasive animal models can be used to determine mechanisms of osteocyte mechanotransduction, at the cell and molecular level, while simultaneously reducing potentially confounding responses such as inflammation/wound-healing. The details of osteocyte mechanotransduction in bone are gradually becoming clearer. In vivo model systems are a key tool in pursing this question. Advances in this field are explored and discussed in this review.

The responsiveness of glucose sensing per se to regulate whole-body glucose homeostasis is dependent on the ability of a rise in glucose to lower hepatic glucose production and increase peripheral glucose uptake in vivo. In both rodents and humans, glucose sensing is lost in diabetes and obesity, but the site(s) of impairment remains elusive. Here, we first report that short-term high-fat feeding disrupts hypothalamic glucose sensing to lower glucose production in rats. Second, leptin administration into the hypothalamus of high-fat–fed rats restored hypothalamic glucose sensing to lower glucose production during a pancreatic (basal insulin)-euglycemic clamp and increased whole-body glucose tolerance during an intravenous glucose tolerance test. Finally, both chemical inhibition of hypothalamic lactate dehydrogenase (LDH) (achieved via hypothalamic LDH inhibitor oxamate infusion) and molecular knockdown of LDHA (achieved via hypothalamic lentiviral LDHA shRNA injection) negated the ability of hypothalamic leptin infusion to enhance glucose sensing to lower glucose production in high fat–fed rats. In summary, our findings illustrate that leptin enhances LDHA-dependent glucose sensing in the hypothalamus to lower glucose production in high-fat–fed rodents in vivo.

The gut microbiota alters energy homeostasis. In parallel, metformin regulates upper small intestinal sodium glucose cotransporter-1 (SGLT1), but whether changes of the microbiota or SGLT1-dependent pathways in the upper small intestine mediate metformin action is unknown. Here we report that upper small intestinal glucose sensing triggers an SGLT1-dependent pathway to lower glucose production in rodents. High-fat diet (HFD) feeding reduces glucose sensing and SGLT1 expression in the upper small intestine. Upper small intestinal metformin treatment restores SGLT1 expression and glucose sensing while shifting the upper small intestinal microbiota partly by increasing the abundance of Lactobacillus. Transplantation of upper small intestinal microbiota from metformin-treated HFD rats to the upper small intestine of untreated HFD rats also increases the upper small intestinal abundance of Lactobacillus and glucose sensing via an upregulation of SGLT1 expression. Thus, we demonstrate that metformin alters upper small intestinal microbiota and impacts a glucose-SGLT1-sensing glucoregulatory pathway.

Impaired glucose homeostasis and energy balance are integral to the pathophysiology of diabetes and obesity. Here we show that administration of a glycine transporter 1 (GlyT1) inhibitor, or molecular GlyT1 knockdown, in the dorsal vagal complex (DVC) suppresses glucose production, increases glucose tolerance and reduces food intake and body weight gain in healthy, obese and diabetic rats. These findings provide proof of concept that GlyT1 inhibition in the brain improves glucose and energy homeostasis. Considering the clinical safety and efficacy of GlyT1 inhibitors in raising glycine levels in clinical trials for schizophrenia, we propose that GlyT1 inhibitors have the potential to be repurposed as a treatment of both obesity and diabetes., Glycine sensing in the dorsal vagal complex (DVC) regulates hepatic glucose production in rodents. Here the authors show that pharmacological and molecular inhibition of glycine reuptake in the DVC potentiates NMDA receptors, and improves metabolic homeostasis in animal models of obesity and diabetes.

Summary Long-chain acyl-CoA synthetase (ACSL)-dependent upper small intestinal lipid metabolism activates pre-absorptive pathways to regulate metabolic homeostasis, but whether changes in the upper small intestinal microbiota alter specific fatty acid-dependent pathways to impact glucose homeostasis remains unknown. We here first find that upper small intestinal infusion of Intralipid, oleic acid, or linoleic acid pre-absorptively increases glucose tolerance and lowers glucose production in rodents. High-fat feeding impairs pre-absorptive fatty acid sensing and reduces upper small intestinal Lactobacillus gasseri levels and ACSL3 expression. Transplantation of healthy upper small intestinal microbiota to high-fat-fed rodents restores L. gasseri levels and fatty acid sensing via increased ACSL3 expression, while L. gasseri probiotic administration to non-transplanted high-fat-fed rodents is sufficient to restore upper small intestinal ACSL3 expression and fatty acid sensing. In summary, we unveil a glucoregulatory role of upper small intestinal L. gasseri that impacts an ACSL3-dependent glucoregulatory fatty acid-sensing pathway.

Evidence continues to emerge detailing the myriad of ways the gut microbiota influences host energy homeostasis. Among the potential mechanisms, short chain fatty acids (SCFAs), the byproducts of microbial fermentation of dietary fibers, exhibit correlative beneficial metabolic effects in humans and rodents, including improvements in glucose homeostasis. The underlying mechanisms, however, remain elusive. We here report that one of the main bacterially produced SCFAs, propionate, activates ileal mucosal free fatty acid receptor 2 to trigger a negative feedback pathway to lower hepatic glucose production in healthy rats in vivo. We further demonstrate that an ileal glucagon-like peptide-1 receptor-dependent neuronal network is necessary for ileal propionate and long chain fatty acid sensing to regulate glucose homeostasis. These findings highlight the potential to manipulate fatty acid sensing machinery in the ileum to regulate glucose homeostasis.

Despite significant progress in understanding the homeostatic regulation of energy balance, successful therapeutic options for curbing obesity remain elusive. One potential target for the treatment of obesity is via manipulation of the gut-brain axis, a complex bidirectional communication system that is crucial in maintaining energy homeostasis. Indeed, ingested nutrients induce secretion of gut peptides that act either via paracrine signaling through vagal and non-vagal neuronal relays, or in an endocrine fashion via entry into circulation, to ultimately signal to the central nervous system where appropriate responses are generated. We review here the current hypotheses of nutrient sensing mechanisms of enteroendocrine cells, including the release of gut peptides, mainly cholecystokinin, glucagon-like peptide-1, and peptide YY, and subsequent gut-to-brain signaling pathways promoting a reduction of food intake and an increase in energy expenditure. Furthermore, this review highlights recent research suggesting this energy regulating gut-brain axis can be influenced by gut microbiota, potentially contributing to the development of obesity.