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Physical parameterizations in global atmospheric and ocean models typically include free parameters that are not theoretically or empirically constrained. New methods are required to determine the optimal parameter combinations for such models in an objective, exhaustive, yet computationally feasible manner. Here we propose to apply computationally inexpensive radial basis function (RBF) surrogate models to minimize a "cost," or error, function of an atmospheric model or a physical parameterization. The RBF is iteratively updated as more input‐output pairs are obtained during the optimization. The approach is used to optimize the eddy‐diffusivity/mass‐flux boundary‐layer parameterization of the convective boundary‐layer in a single‐column model framework. The optimization based on surrogate models is able to identify parameter combinations that reduce the error of the untuned default setting by 41%. The probability to detect a low‐error solution increases rapidly especially over the first tens of single‐column model evaluations. In comparison, a quadratic polynomial model only yields an error reduction of 17% since (a) high‐order parameter interactions are not accounted for and (b) the construction of the polynomial is not based on an iterative sampling approach. The RBF surrogate models achieve this 17% error reduction for 40% of the polynomial model's cost. Interestingly, one of the emerging optimal settings describes a pure mass flux parameterization without eddy‐diffusivity component. A second optimal solution is characterized by a plume fractional area of 20–30% and an eddy‐mixing time scale of ∼700 s. Key Points: Radial basis function (RBF) surrogate models provide an efficient framework to optimize physics parameterizations such as EDMFThe RBF surrogate models detect solutions much better than those provided by a commonly used quadratic polynomial model and are less costlyA multiplume model without eddy‐diffusivity flux emerges as one of the optimal settings for the cloud‐free and cloud‐topped convective PBL [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) constantly monitors nutrient availability in the body and, in particular, in the gastrointestinal (GI) tract to regulate nutrient and energy homeostasis. Extrinsic parasympathetic and sympathetic nerves are crucial for CNS nutrient sensing in the GI tract. These extrinsic afferent nerves detect the nature and amount of nutrients present in the GI tract and relay the information to the brain, which controls energy intake and expenditure accordingly. Dietary fat and fatty acids are sensed through various direct and indirect mechanisms. These sensing processes involve the binding of fatty acids to specific G protein-coupled receptors expressed either on the afferent nerve fibres or on the surface of enteroendocrine cells that release gut peptides, which themselves can modulate afferent nerve activity through their cognate receptors or have endocrine effects directly on the brain. Further dietary fat sensing mechanisms that are related to enterocyte fat handling and metabolism involve the release of several possible chemical mediators such as fatty acid ethanolamides or apolipoprotein A-IV. We here present evidence for yet another mechanism that may be based on ketone bodies resulting from enterocyte oxidation of dietary fat-derived fatty acids. The presently available evidence suggests that sympathetic rather than vagal afferents are involved, but further experiments are necessary to critically examine this concept. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 receptor ( GLP-1R) agonists such as exendin-4 ( Ex-4) affect eating and metabolism and are potential candidates for treating obesity and type II diabetes. In the present study, we tested whether vagal afferents mediate the eating-inhibitory and avoidance-inducing effects of Ex-4. Subdiaphragmatic vagal deafferentation ( SDA) blunted the short-term (< 1 h) but not long-term eating-inhibitory effect of i.p.-infused Ex-4 (0.1 μg/kg) in rats. A dose of 1 μg/kg Ex-4 reduced 0.5, 1, 2 and 4 h cumulative food intake in SDA and sham-operated rats to a similar extent. Paradoxically, SDA but not sham rats developed a conditioned flavour avoidance ( CFA) after i.p. Ex-4 (0.1 μg/kg). SDA completely blunted the induction of c- Fos expression by Ex-4 in the hypothalamic paraventricular nucleus. Ex-4, however, increased the number of c- Fos expressing cells, independent of intact vagal afferents, in the nucleus accumbens and in the central nucleus of the amygdala, the lateral external parabrachial nucleus, the caudal ventrolateral medulla and the dorsal vagal complex. These data suggest that intact vagal afferents are only necessary for the full expression of the early satiating effect of Ex-4 but not for later eating-inhibitory actions, when circulating Ex-4 might reach the brain via the circulation. Our data also dissociate the satiating and avoidance-inducing effects of the low Ex-4 dose tested under our conditions and suggest that vagal afferent signalling may protect against the development of CFA. Taken together, these findings reveal a complex role of vagal afferents in mediating the effects of GLP-1 R activation on ingestive behaviour. [ABSTRACT FROM AUTHOR]

We recently reported that brief, remotely controlled intrameal hepatic-portal vein infusions of glucagon-like peptide-1 (GLP-1) reduced spontaneous meal size in rats. To investigate the neurobehavioural correlates of this effect, we equipped male Sprague-Dawley rats with hepatic-portal vein catheters and assessed (i) the effect on eating of remotely triggered infusions of GLP-1 (1 nmol/kg, 5 min) or vehicle during the first nocturnal meal after 3 h of food deprivation and (ii) the effect of identical infusions performed at dark onset on c-Fos expression in several brain areas involved in the control of eating. GLP-1 reduced (P < 0.05) the size of the first nocturnal meal and increased its satiety ratio. Also, GLP-1 increased (P < 0.05) the number of c-Fos-expressing cells in the nucleus tractus solitarii, the area postrema and the central nucleus of the amygdala, but not in the arcuate or paraventricular hypothalamic nuclei. These data suggest that the nucleus tractus solitarii, the area postrema and the central nucleus of the amygdala play a role in the eating-inhibitory actions of GLP-1 infused into the hepatic-portal vein; it remains to be established whether activation of these brain nuclei reflect satiation, aversion, or both. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that purebred Boran ( Bos indicus) cows and crossbreds of Boran and Holstein respond differently to long-term changes of feeding level in nutrient partitioning to milk and body fat stores. A total of 27 cows of these two genotypes were subjected either to a low or a high feeding level from their first oestrus as heifers until birth of their third calf. Half of the cows of each genotype were then switched to the other feeding level during the third reproduction cycle. If at all, Boran cows responded to a change in the feeding level almost exclusively by a corresponding change in body weight but not milk yield. Crossbred cows kept continuously on the low feeding level had a lower milk yield than those continuously fed the high level, but lost similar amounts of body weight. In crossbred cows, changing the feeding level from high to low was accompanied by a mobilization of body reserves, whereas a change from low to high level resulted mostly in an increase in milk yield. Certain other genotype differences in metabolic response were obvious from differences in body composition and from the metabolic profile either reflected in blood (particularly insulin-like growth factor I) or in adipose tissue (lipoprotein lipase). Reproductive performance differed between genotypes, with shorter lactations associated with earlier occurrences of the first oestrus in the Boran cows. Generally, feeding history appeared to have at least as much influence on energy partitioning as the actual feeding level. In conclusion, purebred Boran cows seem to react to long-term food fluctuations mainly by mobilizing and restoring body fat reserves, whereas cows crossbred with Holstein tend to spend extra energy preferentially for milk production. [ABSTRACT FROM AUTHOR]

Experiments on the host cell spectrum of bovine leukaemia virus (BLV), a retrovirus closely related to the human T-cell leukaemia virus (HTLV), have yielded conflicting data. Currently, BLV is known to infect B cells, whereas its ability to infect other cell types, e.g. monocytes/macrophages, is doubtful. As monocytes/macrophages may have profound effects on the diversity of the T-cell response, we studied the possibility of in vitro infection, using bovine monocytes and SV40-transformed bovine macrophages. Proviral DNA was detected by nested polymerase chain reaction (PCR) from day 1 until the end of the experiments at either day 5 or day 80, depending on the quantity of virus used for infection. In addition, the infection was associated with morphological changes in infected cells as revealed by electron microscopy. The in vitro infection did not significantly change either the expression of surface antigens (CD11b, CD32, and major histocompatibility complex (MHC) class II) or the amounts of cytokine transcripts (interleukin (IL)-1β, tumour necrosis factor (TNF)-α, IL-6 and IL-12p40) with or without lipopolysaccharide (LPS) stimulation. The data suggest that BLV can infect monocytes, but the infection does not seem to influence the function or the phenotype of these cells. Infected monocytes may, however, play a role as a viral reservoir in vivo. [ABSTRACT FROM AUTHOR]

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To further characterize the suppression of feeding that normally accompanies water deprivation and to test whether vasopressin contributes to this hypophagia, food intake, meal patterns and plasma vasopressin concentrations were measured during 24 h or 72 h of water deprivation in pygmy goats. The effects of exogenous vasopressin and of a V1-receptor antagonist on feeding during water deprivation were also assessed. The hypophagia during water deprivation was primarily due to decreases in meal size. The plasma vasopressin concentration increased about 2.5-fold and 10-fold after 24 and 72 h of water deprivation, respectively. Plasma osmolality also increased (measured only after 72 h of water deprivation). Intraperitoneally (ip) injected vasopressin (1.5 μ/kg b. wt.) that previously reduced food intake in goats with ad lib. access to water (Meyer et al., 1989), failed to affect cumulative food intake in water deprived goats, but led to a transient increase in meal size. The V1-receptor antagonist (2.5 μ/kg b. wt., ip) did not affect cumulative food intake or meal patterns either. These findings indicate that endogenous vasopressin is not crucially involved in the hypophagia during water deprivation. The results are in line with the hypothesis that an abnormal prandial increase in the osmolality of the ruminal fluid is a major contributor to the hypophagia during water deprivation. [ABSTRACT FROM AUTHOR]

Pathophysiology of Inappetence 1. Inappetence due to the activation of gastrointestinal and metabolic 'feedback'-signals Many diseases are accompanied by a loss of appetite suggesting that signals which inhibit feeding ('feedback'-signals) are activated during illness. There are gastrointestinal and metabolic 'feedback'-signals. Gastrointestinal 'feedback'-signals can be humoral (gastrointestinal hormones, e. g. Bombesin and Cholezystokinin) or neural (originating from chemo- or mechano-receptors). Metabolic 'feedback'-signals may be derived from hepatic chemoreceptors, which are able to sense the oxidation of various metabolic fuels. The various 'feedback'-signals are supposed to be integrated in the hypothalamus, where prostaglandins might contribute to this process as neuromodulators. 'Feedback'-signals are activated differently during various diseases. Elevated plasma levels of cholecystokinin and a delay in stomach emptying may lead to an activation of gastric 'feedback'-signals during parasitic infections of the gastrointestinal tract. During neoplastic diseases, a metabolic 'feedback'-signal is presumably activated by an increased hepatic oxidation of pyruvate, glucose and free fatty acids. The enhanced synthesis of prostaglandins in the hypothalamus as well as elevated plasma levels of glucagon and adrenaline might contribute to the loss of appetite during infections. Prostaglandins inhibit gastrointestinal motility and thereby activate gastrointestinal 'feedback'-signals. Adrenaline presumably also triggers gastrointestinal 'feedback'-signals, while glucagon most likely activates a metabolic, hepatic 'feedback'-signal. Finally, the increased oxidation of fatty acids in ruminant ketosis might activate a metabolic 'feedback'-signal and thus contribute to the loss of appetite during ketosis. Zusammenfassung Bei vielen Erkrankungen kommt es zur Inappetenz. Im Verlauf der betreffenden Krankheiten werden also offenbar Signale ausgelöst, die die Nahrungsaufnahme hemmen ('Feedback'-Signale). Man kennt gastrointestinale und metabolische 'Feedback'-Signale. Gastrointestinale 'Feedback'-Signale scheinen humoraler (Gastrointestinalhormone, z. B. Bombesin und Cholezystokinin) oder nervaler (von Chemo- und Mechanorezeptoren ausgehend) Natur zu sein. Metabolische 'Feedback'-Signale entstehen vermutlich vorwiegend in hepatischen Chemorezeptoren, die die Oxidation energie-liefernder Substrate registrieren. Man nimmt an, daß 'Feedback'-Signale im Hypothalamus koordiniert werden. Daran scheinen Prostaglandine als Neuromodulatoren beteiligt zu sein. Bei Krankheiten werden die genannten 'Feedback'-Signale auf unterschiedliche Weise ausgelöst bzw. verstärkt. Im Falle von Parasitosen des Magen-Darm-Traktes könnten erhöhte Plasmaspiegel von Cholezystokinin und eine Hemmung der Magenentleerung gastrale 'Feedback'-Signale aktivieren. Im Fall von Neoplasien wird vermutlich über eine Steigerung der hepatischen Oxidation von Pyruvat, Glucose und freien Fettsäuren ein metabolisches 'Feedback'-Signal aktiviert. Bei Infektionen dürften die gesteigerte Prostaglandinsynthese im Hypothalamus sowie erhöhte Plasmaspiegel von Glucagon und Adrenalin zur Inappetenz beitragen. Dabei reduzieren Prostaglandine im Hypothalamus entweder direkt den Verzehr oder hemmen die Magen-Darm-Motorik und lösen damit gastrale 'Feedback'-Signale aus. Adrenalin löst vermutlich ebenfalls gastrointestinale 'Feedback'-Signale aus, während Glucagon wahrscheinlich ein metabolisches, hepatisches 'Feedback'-Signal aktiviert. Bei der Ketose der Wiederkäuer könnte schließlich die gesteigerte Oxidation von freien Fettsäuren ein metabolisches Feedback-Signal auslösen und damit zur Inappetenz bei dieser Erkrankung beitragen. [ABSTRACT FROM AUTHOR]

Pathophysiology of Inappetence 2. Inappetence due to learned taste aversions Man and animals associate malaise with the taste of ingested food. As a consequence, food is rejected due to the formation of a conditioned taste aversion. Nutrient selection in omnivorous species, but also avoidance of toxic or inappropriate food in carnivorous and herbivorous species, is based on such learning mechanisms. Conditioned taste aversions are probably the predominant cause of the lack of appetite accompanying nutrient deficiencies and intoxications. However, malaise which is not caused by ingested food is also associated with the taste of food and leads to food avoidance. Conditioned taste aversions might therefore also contribute to the lack of appetite accompanying other diseases. In particular, this has been shown for neoplastic and parasitic diseases. Zusammenfassung Mensch und Tier assoziieren Störungen des Allgemeinbefindens mit dem Geschmack der aufgenommenen Nahrung. Dies führt zur Ablehnung der betreffenden Nahrung aufgrund einer erlernten Geschmacksaversion. Solche Lernprozesse steuern die Nährstoffselektion bei Omnivoren, dienen aber auch Carnivoren und Herbivoren dazu, unbekömmliches Futter zu meiden. Erlernte Geschmacksaversionen sind wahrscheinlich die wichtigste Ursache der Inappetenz bei Mangelkrankheiten und Intoxikationen. Störungen des Allgemeinbefindens, die nicht durch das aufgenommene Futter verursacht werden, werden jedoch ebenfalls mit dem Geschmack des Futters assoziiert und führen zur Ablehnung desselben. Erlernte Geschmacksaversionen dürften demnach auch zur Inappetenz bei anderen Erkrankungen beitragen. Dies wurde für Parasitosen und Neoplasien experimentell gezeigt. [ABSTRACT FROM AUTHOR]

Peripheral glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) are secreted from enteroendocrine cells, and their plasma concentrations increase in response to eating. While the satiating effect of gut-derived CCK on food-intake control is well documented, the effect of peripheral GLP-1 is less clear. There is evidence that native GLP-1 can inhibit food intake only in the fed state but not in the fasting state. We therefore hypothesized that other gut peptides released during a meal might influence the subsequent effect of endogenous GLP-1 and investigated whether CCK could do so. We found that intraperitoneal injection of CCK in food-restricted mice inhibited food intake during the first 30-minute segment of a 1-hour session of ad libitum chow intake and that mice compensated by increasing their intake during the second half of the session. Importantly, this compensatory behaviour was abolished by an intraperitoneal injection of GLP-1 administered following an intraperitoneal injection of CCK and prior to the 1-hour session. In vivo activation of the free fatty acid 1 (FFA1) receptor with orally administered TAK875 increased plasma CCK concentration and, consistent with the effect of exogenous CCK, we found that prior oral administration of TAK875 increased the eating inhibitory effect of peripherally administered GLP-1. To examine the role of the vagus nerve in this effect, we utilized a saporin-based lesioning procedure to selectively ablate the CCK receptor-expressing gastrointestinal vagal afferent neurones (VANs). We found that the combined anorectic effect of TAK875 and GLP-1 was significantly attenuated in the absence of CCK receptor expressing VANs. Taken together, our results indicate that endogenous CCK interacts with GLP-1 to promote satiation and that activation of the FFA1 receptor can initiate this interaction by stimulating the release of CCK., (© 2021 John Wiley & Sons Ltd.)

Obesity is a well-known risk factor for the development of secondary complications such as type 2 diabetes. However, only a part of the obese population develops secondary metabolic disorders. Here, we identify the transcription factor retinoid-related orphan receptor gamma (RORγ) as a negative regulator of adipocyte differentiation through expression of its newly identified target gene matrix metalloproteinase 3. In vivo differentiation of adipocyte progenitor cells from Rorγ-deficient mice is enhanced and obese Rorγ(-/-) mice show decreased adipocyte sizes. These small adipocytes are highly insulin sensitive, leading to an improved control of circulating free fatty acids. Ultimately, Rorγ(-/-) mice are protected from hyperglycemia and insulin resistance in the state of obesity. In adipose stromal-vascular fraction from obese human subjects, Rorγ expression is correlated with adipocyte size and negatively correlated with adipogenesis and insulin sensitivity. Taken together, our findings identify RORγ as a factor, which controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. RORγ might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance., (Copyright © 2011 EMBO Molecular Medicine.)