Special Issue: "Recent Advances in Ion Channels and Ion Channelopathies".

The aim of this special issue was to showcase recent advanced in understanding ion channel function and dysfunction associated with disease [...].

Maternal Diet High in Linoleic Acid Alters Renal Branching Morphogenesis and mTOR/AKT Signalling Genes in Rat Fetal Kidneys.

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is obtained from the maternal diet during pregnancy, and is essential for normal fetal growth and development. A maternal high-LA (HLA) diet alters maternal and offspring fatty acids, maternal leptin and male/female ratio at embryonic (E) day 20 (E20). We investigated the effects of an HLA diet on embryonic offspring renal branching morphogenesis, leptin signalling, megalin signalling and angiogenesis gene expression. Female Wistar Kyoto rats were fed low-LA (LLA; 1.44% energy from LA) or high-LA (HLA; 6.21% energy from LA) diets during pregnancy and gestation/lactation. Offspring were sacrificed and mRNA from kidneys was analysed by real-time PCR. Maternal HLA decreased the targets involved in branching morphogenesis Ret and Gdnf in offspring, independent of sex. Furthermore, downstream targets of megalin, namely mTOR, Akt3 and Prkab2, were reduced in offspring from mothers consuming an HLA diet, independent of sex. There was a trend of an increase in the branching morphogenesis target Gfra1 in females (p = 0.0517). These findings suggest that an HLA diet during pregnancy may lead to altered renal function in offspring. Future research should investigate the effects an HLA diet has on offspring kidney function in adolescence and adulthood.

Maternal Diet High in Linoleic Acid Alters Offspring Lipids and Hepatic Regulators of Lipid Metabolism in an Adolescent Rat Model.

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is essential for fetal growth and development. A maternal high LA (HLA) diet alters cardiovascular development in adolescent rats and hepatic function in adult rats in a sex-specific manner. We investigated the effects of an HLA diet on adolescent offspring hepatic lipids and hepatic lipid metabolism gene expression, and the ability of the postnatal diet to alter these effects. Female Wistar Kyoto rats were fed low LA (LLA; 1.44% energy from LA) or high LA (HLA; 6.21% energy from LA) diets during pregnancy and gestation/lactation. Offspring, weaned at postnatal day (PN) 25, were fed LLA or HLA and euthanised at PN40 (n = 6-8). Maternal HLA increased circulating uric acid, decreased hepatic cholesterol and increased hepatic Pparg in males, whereas only hepatic Srebf1 and Hmgcr increased in females. Postnatal (post-weaning) HLA decreased liver weight (% body weight) and increased hepatic Hmgcr in males, and decreased hepatic triglycerides in females. Maternal and postnatal HLA had an interaction effect on Lpl, Cpt1a and Pparg in females. These findings suggest that an HLA diet both during and after pregnancy should be avoided to improve offspring disease risk.

Unpacking and validating the "integration" core concept of physiology by an Australian team.

Consensus was reached on seven core concepts of physiology using the Delphi method, including "integration," outlined by the descriptor "cells, tissues, organs, and organ systems interact to create and sustain life." This core concept was unpacked by a team of 3 Australian physiology educators into hierarchical levels, identifying 5 themes and 10 subthemes, up to 1 level deep. The unpacked core concept was then circulated among 23 experienced physiology educators for comments and to rate both level of importance and level of difficulty for each theme and subtheme. Data were analyzed using a one-way ANOVA to compare between and within themes. The main theme (theme 1: the body is organized within a hierarchy of structures, from atoms to molecules, cells, tissues, organs, and organ systems) was almost universally rated as Essential. Interestingly, the main theme was also rated between Slightly Difficult to Not Difficult, which was significantly different from all other subthemes. There were two separate subsets of themes in relation to importance, with three themes rating between Essential and Important and the two other themes rating as Important. Two subsets in the difficulty of the main themes were also identified. While many core concepts can be taught concurrently, Integration requires the application of prior knowledge, with the expectation that learners should be able to apply concepts from "cell-cell communication," "homeostasis," and "structure and function," before understanding the overall Integration core concept. As such, themes from the Integration core concept should be taught within the endmost semesters of a Physiology program.NEW & NOTEWORTHY This article proposes the inclusion of a core concept regarding "integration" into physiology-based curricula, with the descriptor "cells, tissues, organs, and organ systems interact to create and sustain life." This concept expands prior knowledge and applies physiological understanding to real-world scenarios and introduces contexts such as medications, diseases, and aging to the student learning experience. To comprehend the topics within the Integration core concept, students will need to apply learned material from earlier semesters.

Unpacking the "movement of substances" core concept of physiology by an Australian team.

Australia-wide consensus was reached on seven core concepts of physiology. The "movement of substances" core concept with the descriptor "the movement of substances (ions or molecules) is a fundamental process that occurs at all levels of organization in the organism" was unpacked by a team of three Australian physiology educators from the Delphi Task Force into hierarchical levels. There were 10 themes and 23 subthemes arranged in a hierarchy, some 3 levels deep. Using a 5-point Likert scale, the unpacked core concept was then rated for level of importance for students to understand (ranging from 1 = Essential to 5 = Not Important) and level of difficulty for students (ranging from 1 = Very Difficult to 5 = Not Difficult) by the 23 physiology educators from different Australian universities, all with a broad range of teaching and curriculum experience. Survey data were analyzed using a one-way ANOVA to compare between and within concept themes. The main themes all were rated on average as important. There was a wide range of difficulty ratings and more variation for this concept compared with the other core concepts. This may in part be due to the physical forces such as gravity, electrochemistry, resistance, and thermodynamics that underpin this concept, which in themselves are inherently complex. Separation of concepts into subthemes can help prioritize learning activities and time spent on difficult concepts. Embedding of core concepts across curricula will allow commonality and consistency between programs of study and inform learning outcomes, assessment, and teaching and learning activities.NEW & NOTEWORTHY This article unpacks the core concept of the "movement of substances" within the body, with the aim to produce a resource that will help guide the teaching of physiology at tertiary education institutes in Australia. The concept introduces fundamental knowledge of the factors that drive substance movement and then applies them in physiological contexts.

Unpacking and validating the "physiological adaptation" core concept of physiology.

A national Task Force of 25 Australian physiology educators used the Delphi protocol to develop seven physiology core concepts that were agreed to nationally. The aim of the current study was to unpack the "physiological adaptation" core concept with the descriptor "organisms adjust and adapt to acute and chronic changes in the internal and external environments across the lifespan." This core concept was unpacked by three Task Force members and a facilitator into four themes and nine subthemes that encompass the role of stressors and disturbed homeostasis in adaptation and the capacity for, and the nature of, the physiological adaptation. Twenty-two Task Force members then provided feedback and rated the themes and subthemes for level of importance and difficulty for students to learn via an online survey using a five-point Likert scale. Seventeen respondents completed all survey questions. For all themes/subthemes, importance was typically rated 1 (Essential) or 2 (Important) (n = 17, means ±SD ranged from 1.1 ± 0.3 to 2.2 ± 0.9), and difficulty was typically rated 3 (Moderately Difficult) (n = 17, means ranged from 2.9 ± 0.7 to 3.4 ± 0.9). Subtle differences in the proportion of importance scores (n = 17, Fisher's exact: P = 0.004, ANOVA: F12,220 = 2.630, P = 0.003; n = 22, Fisher's exact: P = 0.002, ANOVA: F12,281 = 2.743, P < 0.001), but not difficulty scores, were observed between themes/subthemes, and free-text feedback was minor. The results suggest successful unpacking of the physiological adaptation core concept. The themes and subthemes can inform the design of learning outcomes, assessment, and teaching and learning activities that have commonality and consistency across curricula.NEW & NOTEWORTHY An Australian Task Force of physiology educators identified physiological adaptation as a core concept of physiology. It was subsequently unpacked into four themes and nine subthemes. These were rated, by the Task Force, Essential or Important and Moderately Difficult for students to learn. The themes and subthemes can inform the design of learning outcomes, assessments, and teaching and learning activities that have commonality and consistency across curricula.

Unpacking the renal system component of the "structure and function" core concept of physiology by an Australian team.

An Australia-wide consensus was reached on seven core concepts of physiology, one of which was "structure and function" with the descriptor "Structure and function are intrinsically related to all levels of the organism. In all physiological systems, the structure from a microscopic level to an organ level dictates its function." As a framework for the structure and function core concept, the renal system was unpacked by a team of 5 Australian Physiology educators from different universities with extensive teaching experience into hierarchical levels, with 5 themes and 25 subthemes up to 3 levels deep. Within theme 1, the structures that comprise the renal system were unpacked. Within theme 2, the physiological processes within the nephron such as filtration, reabsorption, and secretion were unpacked. Within theme 3, the processes involved in micturition were unpacked. In theme 4, the structures and processes involved in regulating renal blood flow and glomerular filtration were unpacked; and within theme 5, the role of the kidney in red blood cell production was unpacked. Twenty-one academics rated the difficulty and importance of each theme/subtheme, and results were analyzed using a one-way ANOVA. All identified themes were validated as "essential" to "important"/"moderately important" and rated between "difficult" to "not difficult." A similar framework consisting of structure, physiological processes, physical processes, and regulation can be used to unpack other body systems. Unpacking of the body systems will provide a list of what students should be taught in curricula across Australian universities and inform assessment and learning activities.NEW & NOTEWORTHY This is the first attempt to unpack and validate the "structure and function" core concept in physiology with all Australian educators. We unpacked the renal system into themes with hierarchical levels, which were validated by an experienced team of Australian physiology educators. Our unpacking of the "structure and function" core concept provides a specific framework for educators to apply this important concept in physiology education.

Unpacking and validating the "cell-cell communication" core concept of physiology by an Australian team.

An Australia-wide consensus was reached on seven core concepts of physiology, one of which was cell-cell communication. Three physiology educators from a "core concepts" Delphi task force "unpacked" this core concept into seven different themes and 60 subthemes. Cell-cell communication, previously unpacked and validated, was modified for an Australian audience to include emerging knowledge and adapted to increase student accessibility. The unpacked hierarchical framework for this core concept was rated by 24 physiology educators from separate Australian universities, using a five-point scale for level of importance for student understanding (ranging from 1 = Essential to 5 = Not Important) and level of difficulty (ranging from 1 = Very Difficult to 5 = Not Difficult). Data were analyzed with the Kruskal-Wallis test with Dunn's multiple comparison test. The seven themes were rated within a narrow range of importance (1.13-2.4), with ratings of Essential or Important, and statistically significant differences between the themes (P < 0.0001, n = 7). The variance for the difficulty rating was higher than for importance, ranging from 2.15 (Difficult) to 3.45 (between Moderately Difficult and Slightly Difficult). Qualitatively, it was suggested that some subthemes were similar and that these could be grouped. However, all themes and subthemes were ranked as Important, validating this framework. Once finalized and adopted across Australian universities, the unpacked core concept for cell-cell communication will enable the generation of tools and resources for physiology educators and improvements in consistency across curricula.NEW & NOTEWORTHY Seven core concepts, including cell-cell communication, were identified by an Australian Delphi task force of physiology educators. The previously "unpacked" concept was adapted for Australian educators and students to develop a framework with seven themes and 60 subthemes. The framework was successfully validated by the original Delphi panel of educators and will provide a valuable resource for teaching and learning in Australian universities.

Unpacking and validating the "cell membrane" core concept of physiology by an Australian team.

A task force of physiology educators from 25 Australian universities generated an Australia-wide consensus on seven core concepts for physiology curricula. One adopted core concept was "cell membrane," defined as "Cell membranes determine what substances enter or leave the cell and its organelles. They are essential for cell signaling, transport, and other cellular functions." This concept was unpacked by a team of 3 Australian physiology educators into 4 themes and 33 subthemes arranged in a hierarchical structure up to 5 levels deep. The four themes related to defining the cell membrane, cell membrane structure, transport across cell membranes, and cell membrane potentials. Subsequently, 22 physiology educators with a broad range of teaching experience reviewed and assessed the 37 themes and subthemes for importance for students to understand and the level of difficulty for students on a 5-point Likert scale. The majority (28) of items evaluated were rated as either Essential or Important. Theme 2: cell membrane structure was rated as less important than the other three themes. Theme 4: membrane potential was rated most difficult, while theme 1: defining cell membranes was rated as the easiest. The importance of cell membranes as a key aspect of biomedical education received strong support from Australian educators. The unpacking of the themes and subthemes within the cell membrane core concept provides guidance in the development of curricula and should facilitate better identification of the more challenging aspects within this core concept and help inform the time and resources required to support student learning.NEW & NOTEWORTHY The "cell membrane" core concept was unpacked by a team of Australian physiology educators into a conceptual framework to provide guidance for students and educators. Key themes in the cell membrane core concept were cell membrane definition and structure, transport across cell membranes, and membrane potentials. Australian educators reviewing the framework identified cell membrane as an essential yet relatively simple core concept, suggesting that this is well-placed in foundational physiology courses across a diverse range of degrees.

Mapping the core concepts of physiology across Australian university curricula.

Core concepts in physiology, designed by physiology educators to promote improved learning and teaching, have existed for over a decade. This study aimed to investigate the extent to which a set of 15 core concepts of physiology (developed by Michael and McFarland, U.S.-based educators) are reflected in the learning outcomes (LOs) of units (subjects) comprising physiology curricula in Australian universities. From publicly accessible online information, we identified 17 Australian universities that offered a physiology major for undergraduate degree students and downloaded 788 LOs from the 166 units that comprised the majors. Each LO was blindly mapped against the 15 core concepts by 8 physiology educators from 3 Australian universities. Additionally, text-matching software was employed to match keywords and phrases (identified as descriptors of the 15 core concepts) against the LOs. The frequency of individual words and two-word phrases for each core concept was calculated and ranked. There was variability in rating LOs for the same university among academic mappers; nevertheless, many of the 15 core concepts did not appear to be adequately covered in the LOs. Two core concepts most matched manually were in the top three most mapped by the software. These were, from most common, structure/function and interdependence. Our findings suggest a lack of alignment of LOs with the core concepts across Australian physiology curricula. This highlights the need for Australia-wide agreement on a set of core concepts in physiology as the first step in collaboratively improving assessment and learning and teaching practice in physiology.NEW & NOTEWORTHY This is the first time an existing set of core concepts for physiology, developed by Michael and McFarland (U.S.-based educators), have been mapped against unit (subject) learning outcomes across physiology curricula in Australian universities to gauge uptake and the need for agreement on a set of core concepts in the Australian higher education context.

Unpacking the homeostasis core concept in physiology: an Australian perspective.

Australia-wide consensus was reached on seven core concepts of physiology, which included homeostasis, a fundamental concept for students to understand as they develop their basic knowledge of physiological regulatory mechanisms. The term homeostasis is most commonly used to describe how the internal environment of mammalian systems maintains relative constancy. The descriptor "the internal environment of the organism is actively regulated by the responses of cells, tissues, and organs through feedback systems" was unpacked by a team of three Australian Physiology educators into 5 themes and 18 subthemes arranged in a hierarchy. Using a five-point Likert scale, the unpacked concept was rated by 24 physiology educators from 24 Australian Universities for level of importance and level of difficulty for students. Survey data were analyzed using a one-way ANOVA to compare between and within concept themes and subthemes. There were no differences in main themes for level of importance, with all ratings between essential or important. Theme 1: the organism has regulatory mechanisms to maintain a relatively stable internal environment, a process known as homeostasis was almost unanimously rated as essential. Difficulty ratings for unpacked concept themes averaged between slightly difficult and moderately difficult. The Australian team concurred with published literature that there are inconsistencies in the way the critical components of homeostatic systems are represented and interpreted. We aimed to simplify the components of the concept so that undergraduates would be able to easily identify the language used and build on their knowledge.NEW & NOTEWORTHY The homeostasis core concept of physiology was defined and unpacked by an Australian team with the goal of constructing a resource that will improve learning and teaching of this core physiology concept in an Australian Higher Education context.

Establishing consensus for the core concepts of physiology in the Australian higher education context using the Delphi method.

A set of core concepts ("big ideas") integral to the discipline of physiology are important for students to understand and demonstrate their capacity to apply. We found poor alignment of learning outcomes in programs with physiology majors (or equivalent) from 17 Australian universities and the 15 core concepts developed by a team in the United States. The objective of this project was to reach Australia-wide consensus on a set of core concepts for physiology, which can be embedded in curricula across Australian universities. A four-phase Delphi method was employed, starting with the assembling of a Task Force of physiology educators with extensive teaching and curriculum development expertise from 25 Australian universities. After two online meetings and a survey, the Task Force reached agreement on seven core concepts of physiology and their descriptors, which were then sent out to the physiology educator community across Australia for agreement. The seven core concepts and their associated descriptions were endorsed through this process (n = 138). In addition, embedding the core concepts across the curriculum was supported by both Task Force members (85.7%) and educators (82.1%). The seven adopted core concepts of human physiology were Cell Membrane, Cell-Cell Communication, Movement of Substances, Structure and Function, Homeostasis, Integration, and Physiological Adaptation. The core concepts were subsequently unpacked into themes and subthemes. If adopted, these core concepts will result in consistency across curricula in undergraduate physiology programs and allow for future benchmarking.NEW & NOTEWORTHY This is the first time Australia-wide agreement has been reached on the core concepts of physiology with the Delphi method. Embedding of the core concepts will result in consistency in physiology curricula, improvements to teaching and learning, and benchmarking across Australian universities.

Changes in Essential Fatty Acids and Ileal Genes Associated with Metabolizing Enzymes and Fatty Acid Transporters in Rodent Models of Cystic Fibrosis.

Cystic fibrosis (CF), the result of mutations in the CF transmembrane conductance regulator (CFTR), causes essential fatty acid deficiency. The aim of this study was to characterize fatty acid handling in two rodent models of CF; one strain which harbors the loss of phenylalanine at position 508 (Phe508del) in CFTR and the other lacks functional CFTR (510X). Fatty acid concentrations were determined using gas chromatography in serum from Phe508del and 510X rats. The relative expression of genes responsible for fatty acid transport and metabolism were quantified using real-time PCR. Ileal tissue morphology was assessed histologically. There was an age-dependent decrease in eicosapentaenoic acid and the linoleic acid:α-linolenic acid ratio, a genotype-dependent decrease in docosapentaenoic acid (n-3) and an increase in the arachidonic acid:docosahexaenoic acid ratio in Phe508del rat serum, which was not observed in 510X rats. In the ileum, Cftr mRNA was increased in Phe508del rats but decreased in 510X rats. Further, Elvol2, Slc27a1, Slc27a2 and Got2 mRNA were increased in Phe508del rats only. As assessed by Sirius Red staining, collagen was increased in Phe508del and 510X ileum. Thus, CF rat models exhibit alterations in the concentration of circulating fatty acids, which may be due to altered transport and metabolism, in addition to fibrosis and microscopic structural changes in the ileum.

Treatment of Diet-Induced Obese Rats with CB2 Agonist AM1241 or CB2 Antagonist AM630 Reduces Leptin and Alters Thermogenic mRNA in Adipose Tissue.

Diet-induced obesity (DIO) is a contributor to co-morbidities, resulting in alterations in hormones, lipids, and low-grade inflammation, with the cannabinoid type 2 receptor (CB2) contributing to the inflammatory response. The effects of modulating CB2 with pharmacological treatments on inflammation and adaptations to the obese state are not known. Therefore, we aimed to investigate the molecular mechanisms in adipose tissue of CB2 agonism and CB2 antagonism treatment in a DIO model. Male Sprague Dawley rats were placed on a high-fat diet (HFD) (21% fat) for 9 weeks, then received daily intraperitoneal injections with a vehicle, AM630 (0.3 mg/kg), or AM1241 (3 mg/kg), for a further 6 weeks. AM630 or AM1241 treatment in DIO rats did not alter their body weight, food intake, or liver weight, and it had no effect on their numerous circulating cytokines or peri-renal fat pad mass. AM1241 decreased heart weight and BAT weight; both treatments (AM630 or AM1241) decreased plasma leptin levels, while AM630 also decreased plasma ghrelin and GLP-1 levels. Both treatments decreased Adrb3 and TNF-α mRNA levels in eWAT and TNF-α levels in pWAT. AM630 treatment also decreased the mRNA levels of Cnr2, leptin, and Slc2a4 in eWAT. In BAT, both treatments decreased leptin, UCP1, and Slc2a4 mRNA levels, with AM1241 also decreasing Adrb3, IL1ß, and PRDM16 mRNA levels, and AM630 increasing IL6 mRNA levels. In DIO, CB2 agonist and CB2 antagonist treatment reduces circulating leptin in the absence of weight loss and modulates the mRNA responsible for thermogenesis.

Maternal diet high in linoleic acid alters offspring fatty acids and cardiovascular function in a rat model.

Linoleic acid (LA), an essential n-6 fatty acid (FA), is critical for fetal development. We investigated the effects of maternal high LA (HLA) diet on offspring cardiac development and its relationship to circulating FA and cardiovascular function in adolescent offspring, and the ability of the postnatal diet to reverse any adverse effects. Female Wistar Kyoto rats were fed low LA (LLA; 1·44 % energy from LA) or high LA (HLA; 6·21 % energy from LA) diets for 10 weeks before pregnancy and during gestation/lactation. Offspring, weaned at postnatal day 25, were fed LLA or HLA diets and euthanised at postnatal day 40 (n 6-8). Maternal HLA diet decreased circulating total cholesterol and HDL-cholesterol in females and decreased total plasma n-3 FA in males, while maternal and postnatal HLA diets decreased total plasma n-3 FA in females. α-Linolenic acid (ALA) and EPA were decreased by postnatal but not maternal HLA diets in both sexes. Maternal and postnatal HLA diets increased total plasma n-6 and LA, and a maternal HLA diet increased circulating leptin, in both male and female offspring. Maternal HLA decreased slopes of systolic and diastolic pressure-volume relationship (PVR), and increased cardiac Col1a1, Col3a1, Atp2a1 and Notch1 in males. Maternal and postnatal HLA diets left-shifted the diastolic PVR in female offspring. Coronary reactivity was altered in females, with differential effects on flow repayment after occlusion. Thus, maternal HLA diets impact lipids, FA and cardiac function in offspring, with postnatal diet modifying FA and cardiac function in the female offspring.

Role for animal models in understanding essential fatty acid deficiency in cystic fibrosis.

Essential fatty acid deficiency has been observed in most patients with Cystic Fibrosis (CF); however, pancreatic supplementation does not restore the deficiency, suggesting a different pathology independent of the pancreas. At this time, the underlying pathological mechanisms are largely unknown. Essential fatty acids are obtained from the diet and processed by organs including the liver and intestine, two organs significantly impacted by mutations in the cystic fibrosis transmembrane conductance regulator gene (Cftr). There are several CF animal models in a variety of species that have been developed to investigate molecular mechanisms associated with the CF phenotype. Specifically, global and systemic mutations in Cftr which mimic genotypic changes identified in CF patients have been generated in mice, rats, sheep, pigs and ferrets. These mutations produce CFTR proteins with a gating defect, trafficking defect, or an absent or inactive CFTR channel. Essential fatty acids are critical to CFTR function, with a bidirectional relationship between CFTR and essential fatty acids proposed. Currently, there are limited analyses on the essential fatty acid status in most of these animal models. Of interest, in the mouse model, essential fatty acid status is dependent on the genotype and resultant phenotype of the mouse. Future investigations should identify an optimal animal model that has most of the phenotypic changes associated with CF including the essential fatty acid deficiencies, which can be used in the development of therapeutics.

Early Life Nutrition and the Development of Offspring Metabolic Health.

The developmental origins of health and disease (DOHaD) hypothesis describes the effects of parental perturbations around the periconception, pregnancy, and perinatal window that may lead to changes in offspring development and an increased risk of disease [...].

CB1 Ligand AM251 Induces Weight Loss and Fat Reduction in Addition to Increased Systemic Inflammation in Diet-Induced Obesity.

Diet-induced obesity (DIO) reduces fatty acid oxidation in skeletal muscle and decreases circulating levels of adiponectin. Endocannabinoid signaling is overactive in obesity, with some effects abated by antagonism of cannabinoid receptor 1 (CB1). This research aimed to determine if treatment with the global CB1 antagonist/inverse agonist, AM251, in high-fat diet (HFD) fed rats influenced adiponectin signaling in skeletal muscle and a "browning" of white adipose tissue (WAT) defined by UCP1 expression levels. Male Sprague Dawley rats consumed an HFD (21% fat) for 9 weeks before receiving daily intraperitoneal injections with vehicle or AM251 (3 mg/kg) for 6 weeks. mRNA expression of genes involved in metabolic functions were measured in skeletal muscle and adipose tissue, and blood was harvested for the measurement of hormones and cytokines. Muscle citrate synthase activity was also measured. AM251 treatment decreased fat pad weight (epididymal, peri-renal, brown), and plasma levels of leptin, glucagon, ghrelin, and GLP-1, and increased PAI-1 along with a range of pro-inflammatory and anti-inflammatory cytokines; however, AM251 did not alter plasma adiponectin levels, skeletal muscle citrate synthase activity or mRNA expression of the genes measured in muscle. AM251 treatment had no effect on white fat UCP1 expression levels. AM251 decreased fat pad mass, altered plasma hormone levels, but did not induce browning of WAT defined by UCP1 mRNA levels or alter gene expression in muscle treated acutely with adiponectin, demonstrating the complexity of the endocannabinoid system and metabolism. The CB1 ligand AM251 increased systemic inflammation suggesting limitations on its use in metabolic disorders.

Sex-Specific Differences in Lysine, 3-Hydroxybutyric Acid and Acetic Acid in Offspring Exposed to Maternal and Postnatal High Linoleic Acid Diet, Independent of Diet.

BACKGROUND: Linoleic acid (LA) is an essential polyunsaturated fatty acid (PUFA) that is required for foetal growth and development. Excess intake of LA can be detrimental for metabolic health due to its pro-inflammatory properties; however, the effect of a diet high in LA on offspring metabolites is unknown. In this study, we aimed to determine the role of maternal or postnatal high linoleic acid (HLA) diet on plasma metabolites in adult offspring. METHODS: Female Wistar Kyoto (WKY) rats were fed with either low LA (LLA) or HLA diet for 10 weeks prior to conception and during gestation/lactation. Offspring were weaned at postnatal day 25 (PN25), treated with either LLA or HLA diets and sacrificed at PN180. Metabolite analysis was performed in plasma samples using Nuclear Magnetic Resonance. RESULTS: Maternal and postnatal HLA diet did not alter plasma metabolites in male and female adult offspring. There was no specific clustering among different treatment groups as demonstrated by principal component analysis. Interestingly, there was clustering among male and female offspring independent of maternal and postnatal dietary intervention. Lysine was higher in female offspring, while 3-hydroxybutyric acid and acetic acid were significantly higher in male offspring. CONCLUSION: In summary, maternal or postnatal HLA diet did not alter the plasma metabolites in the adult rat offspring; however, differences in metabolites between male and female offspring occurred independently of dietary intervention.

Maternal and Postnatal High Linoleic Acid Diet Impacts Lipid Metabolism in Adult Rat Offspring in a Sex-Specific Manner.

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is essential for fetal growth and development. We aimed to investigate the effect of maternal and postnatal high LA (HLA) diet on plasma FA composition, plasma and hepatic lipids and genes involved in lipid metabolism in the liver of adult offspring. Female rats were fed with low LA (LLA; 1.44% LA) or HLA (6.21% LA) diets for 10 weeks before pregnancy, and during gestation/lactation. Offspring were weaned at postnatal day 25 (PN25), fed either LLA or HLA diets and sacrificed at PN180. Postnatal HLA diet decreased circulating total n-3 PUFA and alpha-linolenic acid (ALA), while increased total n-6 PUFA, LA and arachidonic acid (AA) in both male and female offspring. Maternal HLA diet increased circulating leptin in female offspring, but not in males. Maternal HLA diet decreased circulating adiponectin in males. Postnatal HLA diet significantly decreased aspartate transaminase (AST) in females and downregulated total cholesterol, HDL-cholesterol and triglycerides in the plasma of males. Maternal HLA diet downregulated the hepatic mRNA expression of Hmgcr in both male and female offspring and decreased the hepatic mRNA expression of Cpt1a and Acox1 in females. Both maternal and postnatal HLA diet decreased hepatic mRNA expression of Cyp27a1 in females. Postnatal diet significantly altered circulating fatty acid concentrations, with sex-specific differences in genes that control lipid metabolism in the adult offspring following exposure to high LA diet in utero.