Body Energy Homeostasis Research Articles

6509 IGF-1 receptor and insulin receptor in LepRb neurons coordinates body growth, reproduction, and metabolism

Abstract Disclosure: M. Wang: None. J.W. Hill: None. Growth and reproduction are tightly linked. Growth hormone (GH) deficiency results in a profound suppression of postnatal growth accompanied by severely delayed puberty and reproductive senescence, while GH excess is correlated with the reverse. The specific mechanism underlying this delay is undefined. Although leptin receptor (LepRb)-expressing neurons are known to link body growth and reproduction, the role of insulin-like growth factor 1 receptor (IGF1R) signaling in LepRb neuron function is unknown. Previous studies have shown that IGF-1 and insulin can bind to each other’s receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we created mice lacking IGF1R exclusively in LepRb neurons (IGF1RLepRb mice) and mice simultaneously lacking IGF1R and IR in LepRb neurons (IGF1R/IRLepRb mice) to test if IGF1R and insulin receptor (IR) cooperatively regulate metabolic and reproductive functions. IGF1RLepRb and IGF1R/IRLepRb mice displayed delayed onset of puberty and impaired fertility in both sexes, which suggested that both IGF1R and IR in LepRb neurons are required for normal reproduction. Additionally, we found transient growth retardation in IGF1RLepRb and IGF1R/IRLepRb mice. Loss of IGF1R in LepRb neurons led to lower serum IGF-1 and GH levels in male mice and impaired trabecular and cortical bone development in mice of both sexes. Only transient and mild changes were noticed in the body weight. However, we found IGF1R and IR in LepRb neurons jointly regulate body mass composition, energy homeostasis and glucose homeostasis, as shown by elevated fat mass composition, low energy expenditure and low physical activity in IGF1R/IRLepRb mice. Taken together, these studies identify the unique and cooperative role of LepRb IGF1R and IRs in the regulation of body growth, reproduction, and metabolism. Presentation: 6/3/2024

Tangeretin Enhances Muscle Endurance and Aerobic Metabolism in Mice via Targeting AdipoR1 to Increase Oxidative Myofibers.

Slow oxidative myofibers play an important role in improving muscle endurance performance and maintaining body energy homeostasis. However, the targets and means to regulate slow oxidative myofibers proportion remain unknown. Here, we show that tangeretin (TG), a natural polymethoxylated flavone, significantly activates slow oxidative myofibers-related gene expression and increases type I myofibers proportion, resulting in improved endurance performance and aerobic metabolism in mice. Proteomics, molecular dynamics, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) investigations revealed that TG can directly bind to adiponectin receptor 1 (AdipoR1). Using AdipoR1-knockdown C2C12 cells and muscle-specific AdipoR1-knockout mice, we found that the positive effect of TG on regulating slow oxidative myofiber related markers expression is mediated by AdipoR1 and its downstream AMPK/PGC-1α pathway. Together, our data uncover TG as a natural compound that regulates the identity of slow oxidative myofibers via targeting the AdipoR1 signaling pathway. These findings further unveil the new function of TG in increasing the proportion of slow oxidative myofibers and enhancing skeletal muscle performance.

Immune metabolic mechanisms of acupuncture in improving glycolipid metabolic disorders explored through pancreatic adipose tissue.

Pancreatic adipose tissue serves as a crucial structural basis for the development of glycolipid metabolic disorders. Understanding the mechanisms underlying pancreatic adipose tissue infiltration and regulatory strategies is essential for early intervention in glycolipid metabolic disorders. Pancreatic adipose tissue functions as a significant medium linking systemic immune metabolism, while the pancreatic vascular system emerges as a novel target for sensing pancreatic immune responses and maintaining the body's energy homeostasis, collectively participating in the development of glycolipid metabolic disorders. Acupuncture possesses potential effects in modulating the interaction between resident macrophages and adipocytes in the pancreas, leading to the reversible reduction of excessive pancreatic adipose accumulation, with its action being vascular-dependent.

Responses and correlation among ER stress, Ca2+ homeostasis, and fatty acid metabolism in Penaeus vannamei under ammonia stress

The role of endoplasmic reticulum (ER) stress, Ca2+ homeostasis, and fatty acid metabolism in the environmental adaptation of aquatic animals is significant, but further confirmation of the relationship between these factors is needed. This study aimed to investigate the responses and correlations among ER stress, Ca2+ homeostasis, and fatty acid metabolism in Penaeus vannamei under ammonia stress. A total of 640 P. vannamei weighing 3.0 ± 0.4 g were selected and exposed to different total ammonia concentrations (0 mg/L for the control group and 3.80, 7.60, and 11.40 mg/L for the stress groups). The experiment involved a 96 h ammonia stress period to assess indicators related to ER stress, Ca2+ homeostasis, and fatty acid metabolism. The experimental results revealed that after 12 h, exposure to ammonia induced the ER stress response in the hepatopancreas of the shrimp. The groups exposed to concentrations of 3.8 mg/L and 7.6 mg/L exhibited an increase in ER Ca2+ efflux, a decrease in influx, an elevation in mitochondrial Ca2+ influx, an enhanced energy demand within the organism, and substantial consumption of triglycerides. The 11.3 mg/L group exhibited a significant enhancement in fatty acid metabolism. At 24 h, the ER stress response induced by ammonia in the shrimp exhibited a gradual recovery. In the 7.6 mg/L and 11.3 mg/L groups, the ER Ca2+ influx and efflux exhibited significant enhancements, while the mitochondrial Ca2+ influx decreased and the organism's energy demand increased. Moreover, there was a substantial enhancement in fatty acid metabolism. At 48 h, the ER stress response disappeared in each stress group, ER Ca2+ efflux was reduced, triglycerides were consumed, and the body's energy homeostasis was basically restored. At 96 h, a stress response reoccurred in the ER in each stress group, resulting in increased influx of Ca2+ into the ER, augmented energy demand within the organism, and notable enhancement in fatty acid metabolism. Pearson correlation analysis revealed a significant positive correlation between the NH3-N content in the hepatopancreas and the expression of ER stress-related genes, as well as between ER Ca2+ influx/efflux and energy homeostasis/fatty acid metabolism. The findings indicate that the stress induced by ammonia triggers an ER stress response in P. vannamei, resulting in ER Ca2+ efflux and mitochondrial Ca2+ influx, which, in turn, enhances fatty acid metabolism to generate additional energy for adaptation in stressful environments. This study contributes to a deeper understanding of the environmental adaptability of P. vannamei in the context of Ca2+ homeostasis.

Adipose Tissue, Non-Communicable Diseases, and Physical Exercise: An Imperfect Triangle.

The study of adipose tissue has received considerable attention due to its importance not just in maintaining body energy homeostasis but also in playing a role in a number of other physiological processes. Beyond storing energy, adipose tissue is important in endocrine, immunological, and neuromodulatory functions, secreting hormones that participate in the regulation of energy homeostasis. An imbalance of these functions will generate structural and functional changes in the adipose tissue, favoring the secretion of deleterious adipocytokines that induce a pro-inflammatory state, allowing the development of metabolic and cardiovascular diseases and even some types of cancer. A common theme worldwide has been the development of professional guidelines for the control and treatment of obesity, with emphasis on hypocaloric diets and exercise. The aim of this review is to examine the pathophysiological mechanisms of obesity, considering the relationship among adipose tissue and two aspects that contribute positively or negatively to keeping a healthy body homeostasis, namely, exercise and noninfectious diseases. We conclude that the relationship of these aspects does not have homogeneous effects among individuals. Nevertheless, it is possible to establish some common mechanisms, like a decrease in pro-inflammatory markers in the case of exercise, and an increase in chronic inflammation in non-communicable diseases. An accurate diagnosis might consider the particular variables of a patient, namely their molecular profile and how it affects its metabolism, routines, and lifestyle; their underling health conditions; and probably even the constitution of their microbiome. We foresee that the development and accessibility of omics approaches and precision medicine will greatly improve the diagnosis, treatment, and successful outcomes for obese patients.

Skeletal muscle-secreted DLPC orchestrates systemic energy homeostasis by enhancing adipose browning

MyoD is a skeletal muscle-specifically expressed transcription factor and plays a critical role in regulating myogenesis during muscle development and regeneration. However, whether myofibers-expressed MyoD exerts its metabolic function in regulating whole body energy homeostasis in vivo remains largely unknown. Here, we report that genetic deletion of Myod in male mice enhances the oxidative metabolism of muscle and, intriguingly, renders the male mice resistant to high fat diet-induced obesity. By performing lipidomic analysis in muscle-conditioned medium and serum, we identify 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) as a muscle-released lipid that is responsible for MyoD-orchestrated body energy homeostasis in male Myod KO mice. Functionally, the administration of DLPC significantly ameliorates HFD-induced obesity in male mice. Mechanistically, DLPC is found to induce white adipose browning via lipid peroxidation-mediated p38 signaling in male mice. Collectively, our findings not only uncover a novel function of MyoD in controlling systemic energy homeostasis through the muscle-derived lipokine DLPC but also suggest that the DLPC might have clinical potential for treating obesity in humans.

Selegiline Modulates Lipid Metabolism by Activating AMPK Pathways of Epididymal White Adipose Tissues in HFD-Fed Obese Mice.

Obesity, as a major cause of many chronic diseases such as diabetes, cardiovascular disease, and cancer, is among the most serious health problems. Increased monoamine oxidase (MAO) activity has been observed in the adipose tissue of obese humans and animals. Although previous studies have already demonstrated the potential of MAO-B inhibitors as a treatment for this condition, the mechanism of their effect has been insufficiently elucidated. In this study, we investigated the anti-obesity effect of selegiline, a selective MAO-B inhibitor, using in vivo animal models. The effect was evaluated through an assessment of body energy homeostasis, glucose tolerance tests, and biochemical analysis. Pharmacological inhibition of MAO-B by selegiline was observed to reduce body weight and fat accumulation, and improved glucose metabolism without a corresponding change in food intake, in HFD-fed obese mice. We also observed that both the expression of adipogenenic markers, including C/EBPα and FABP4, and lipogenic markers such as pACC were significantly reduced in epididymal white adipose tissues (eWATs). Conversely, increased expression of lipolytic markers such as ATGL and pHSL and AMPK phosphorylation were noted. Treating obese mice with selegiline significantly increased expression levels of UCP1 and promoted eWAT browning, indicating increased energy expenditure. These results suggest that selegiline, by inhibiting MAO-B activity, is a potential anti-obesity treatment.

Peroxisome proliferator-activated receptors as therapeutic target for cancer.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor family. There are three subtypes of PPARs, including PPAR-α, PPAR-β/δ and PPAR-γ. They are expressed in different tissues and act by regulating the expression of target genes in the form of binding to ligands. Various subtypes of PPAR have been shown to have significant roles in a wide range of biological processes including lipid metabolism, body energy homeostasis, cell proliferation and differentiation, bone formation, tissue repair and remodelling. Recent studies have found that PPARs are closely related to tumours. They are involved in cancer cell growth, angiogenesis and tumour immune response, and are essential components in tumour progression and metastasis. As such, they have become a target for cancer therapy research. In this review, we discussed the current state of knowledge on the involvement of PPARs in cancer, including their role in tumourigenesis, the impact of PPARs in tumour microenvironment and the potential of using PPARs combinational therapy to treat cancer by targeting essential signal pathways, or as adjuvants to boost the effects of current chemo and immunotherapies. Our review highlights the complexity of PPARs in cancer and the need for a better understanding of the mechanism in order to design effective cancer therapies.

Determining the Potential Roles of Branched-Chain Amino Acids in the Regulation of Muscle Growth in Common Carp (Cyprinus carpio) Based on Transcriptome and MicroRNA Sequencing.

Branched-chain amino acids (BCAAs) can be critically involved in skeletal muscle growth and body energy homeostasis. Skeletal muscle growth is a complex process; some muscle-specific microRNAs (miRNAs) are involved in the regulation of muscle thickening and muscle mass. Additionally, the regulatory network between miRNA and messenger RNA (mRNA) in the modulation of the role of BCAAs on skeletal muscle growth in fish has not been studied. In this study, common carp was starved for 14 days, followed by a 14-day gavage therapy with BCAAs, to investigate some of the miRNAs and genes that contribute to the regulation of normal growth and maintenance of skeletal muscle in response to short-term BCAA starvation stress. Subsequently, the transcriptome and small RNAome sequencing of carp skeletal muscle were performed. A total of 43,414 known and 1,112 novel genes were identified, in addition to 142 known and 654 novel miRNAs targeting 22,008 and 33,824 targets, respectively. Based on their expression profiles, 2,146 differentially expressed genes (DEGs) and 84 differentially expressed miRNA (DEMs) were evaluated. Kyoto Encyclopedia of Genes and Genome pathways, including the proteasome, phagosome, autophagy in animals, proteasome activator complex, and ubiquitin-dependent protein catabolic process, were enriched for these DEGs and DEMs. Our findings revealed the role of atg5, map1lc3c, ctsl, cdc53, psma6, psme2, myl9, and mylk in skeletal muscle growth, protein synthesis, and catabolic metabolism. Furthermore, miR-135c, miR-192, miR-194, and miR-203a may play key roles in maintaining the normal activities of the organism by regulating genes related to muscle growth, protein synthesis, and catabolism. This study on transcriptome and miRNA reveals the potential molecular mechanisms underlying the regulation of muscle protein deposition and provides new insights into genetic engineering techniques to improve common carp muscle development.

Maternal high fat diets: impacts on offspring obesity and epigenetic hypothalamic programming.

Maternal high-fat diet (HFD) during pregnancy is associated with rapid weight gain and fetal fat mass increase at an early stage. Also, HFD during pregnancy can cause the activation of proinflammatory cytokines. Maternal insulin resistance and inflammation lead to increased adipose tissue lipolysis, and also increased free fatty acid (FFA) intake during pregnancy (˃35% of energy from fat) cause a significant increase in FFA levels in the fetus. However, both maternal insulin resistance and HFD have detrimental effects on adiposity in early life. As a result of these metabolic alterations, excess fetal lipid exposure may affect fetal growth and development. On the other hand, increase in blood lipids and inflammation can adversely affect the development of the liver, adipose tissue, brain, skeletal muscle, and pancreas in the fetus, increasing the risk for metabolic disorders. In addition, maternal HFD is associated with changes in the hypothalamic regulation of body weight and energy homeostasis by altering the expression of the leptin receptor, POMC, and neuropeptide Y in the offspring, as well as altering methylation and gene expression of dopamine and opioid-related genes which cause changes in eating behavior. All these maternal metabolic and epigenetic changes may contribute to the childhood obesity epidemic through fetal metabolic programming. Dietary interventions, such as limiting dietary fat intake <35% with appropriate fatty acid intake during the gestation period are the most effective type of intervention to improve the maternal metabolic environment during pregnancy. Appropriate nutritional intake during pregnancy should be the principal goal in reducing the risks of obesity and metabolic disorders.

Prenatal benzene exposure in mice alters offspring hypothalamic development predisposing to metabolic disease in later life

Maternal exposure to environmental contaminants during pregnancy poses a significant threat to a developing fetus, as these substances can easily cross the placenta and disrupt the neurodevelopment of offspring. Specifically, the hypothalamus is essential in the regulation of metabolism, notably during critical windows of development. An abnormal hormonal and inflammatory milieu during development can trigger persistent changes in the function of hypothalamic circuits, leading to long-lasting effects on the body's energy homeostasis and metabolism. We recently demonstrated that gestational exposure to clinically relevant levels of benzene induces severe metabolic dysregulation in the offspring. Given the central role of the hypothalamus in metabolic control, we hypothesized that prenatal exposure to benzene impacts hypothalamic development, contributing to the adverse metabolic effects in the offspring. C57BL/6JB dams were exposed to benzene at 50 ppm in the inhalation chambers exclusively during pregnancy (from E0.5 to E19). Transcriptomic analysis of the exposed offspring at postnatal day 21 (P21) revealed hypothalamic changes in genes related to metabolic regulation, inflammation, and neurodevelopment exclusively in males. Moreover, the hypothalamus of prenatally benzene-exposed male offspring displayed alterations in orexigenic and anorexigenic projections, impairments in leptin signaling, and increased microgliosis. Additional exposure to benzene during lactation did not promote further microgliosis or astrogliosis in the offspring, while the high-fat diet (HFD) challenge in adulthood exacerbated glucose metabolism and hypothalamic inflammation in benzene-exposed offspring of both sexes. These findings reveal the persistent adverse effects of prenatal benzene exposure on hypothalamic circuits and neuroinflammation, predisposing the offspring to long-lasting metabolic health conditions.

Glucocorticoid Receptor and Ovarian Cancer: From Biology to Therapeutic Intervention

Ovarian cancer (OC) is the leading cause of death from gynecological malignancies worldwide. Fortunately, recent advances in OC biology and the discovery of novel therapeutic targets have led to the development of novel therapeutic agents that may improve the outcome of OC patients. The glucocorticoid receptor (GR) is a ligand-dependent transcriptional factor known for its role in body stress reactions, energy homeostasis and immune regulation. Notably, evidence suggests that GR may play a relevant role in tumor progression and may affect treatment response. In cell culture models, administration of low levels of glucocorticoids (GCs) suppresses OC growth and metastasis. Conversely, high GR expression has been associated with poor prognostic features and long-term outcomes in patients with OC. Moreover, both preclinical and clinical data have shown that GR activation impairs the effectiveness of chemotherapy by inducing the apoptotic pathways and cell differentiation. In this narrative review, we summarize data related to the function and role of GR in OC. To this aim, we reorganized the controversial and fragmented data regarding GR activity in OC and herein describe its potential use as a prognostic and predictive biomarker. Moreover, we explored the interplay between GR and BRCA expression and reviewed the latest therapeutic strategies such as non-selective GR antagonists and selective GR modulators to enhance chemotherapy sensitivity, and to finally provide new treatment options in OC patients.

Adipose tissue metabolic changes in chronic kidney disease.

Adipose tissue is a complex organ whose functions go beyond being an energy reservoir to sustain proper body energy homeostasis. Functioning as an endocrine organ, the adipose tissue has an active role in the body's metabolic balance regulation through several secreted factors generally termed as adipokines. Thus, adipose tissue dysregulation in chronic kidney disease (CKD) can have a deep impact in the pathophysiology of diseases associated with metabolic dysregulation including metabolic syndrome, insulin resistance (IR), atherosclerosis, and even cachexia. CKD is a progressive disorder linked to increased morbidity and mortality. Despite being characterized by renal function loss, CKD is accompanied by metabolic disturbances such as dyslipidemia, protein energy wasting, chronic low-grade inflammation, IR, and lipid redistribution. Thus far, the mechanisms by which these changes occur and the role of adipose tissue in CKD development and progression are unclear. Further understanding of how these factors develop could have implications for the management of CKD by helping identify pharmacological targets to improve CKD outcomes.

Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation

Brown adipose tissue (BAT) plays a pivotal role in maintaining body temperature and energy homeostasis. BAT dysfunction is associated with impaired metabolic health. Here, we show that Ssu72 phosphatase is essential for mRNA translation of genes required for thermogenesis in BAT. Ssu72 is found to be highly expressed in BAT among adipose tissue depots, and the expression level of Ssu72 is increased upon acute cold exposure. Mice lacking adipocyte Ssu72 exhibit cold intolerance during acute cold exposure. Mechanistically, Ssu72 deficiency alters cytosolic mRNA translation program through hyperphosphorylation of eIF2α and reduces translation of mitochondrial oxidative phosphorylation (OXPHOS) subunits, resulting in mitochondrial dysfunction and defective thermogenesis in BAT. In addition, metabolic dysfunction in Ssu72-deficient BAT returns to almost normal after restoring Ssu72 expression. In summary, our findings demonstrate that cold-responsive Ssu72 phosphatase is involved in cytosolic translation of key thermogenic effectors via dephosphorylation of eIF2α in brown adipocytes, providing insights into metabolic benefits of Ssu72.

Quantitative Proteomic Analysis of Tibetan Pig Livers at Different Altitudes.

In this study, the differences in protein profiles between the livers of Shannan Tibetan pigs (SNT), Linzhi Tibetan pigs (LZT) and Jiuzhaigou Tibetan pigs (JZT) were comparatively analyzed by tandem mass spectrometry-labeling quantitative proteomics. A total of 6804 proteins were identified: 6471 were quantified and 1095 were screened as differentially expressed proteins (DEPs). Bioinformatics analysis results show that, compared with JZT livers, up-regulated DEPs in SNT and LZT livers mainly promoted hepatic detoxification through steroid hormone biosynthesis and participated in lipid metabolism to maintain body energy homeostasis, immune response and immune regulation, while down-regulated DEPs were mainly involved in lipid metabolism and immune regulation. Three proteases closely related to hepatic fatty acid oxidation were down-regulated in enzymatic activity, indicating higher levels of lipid oxidation in SNT and LZT livers than in JZT livers. Down-regulation of the expression of ten immunoglobulins suggests that JZT are more susceptible to autoimmune diseases. It is highly likely that these differences in lipid metabolism and immune-related proteins are in response to the ecological environment at different altitudes, and the findings contribute to the understanding of the potential molecular link between Tibetan pig livers and the environment.

Deciphering the chromatin organization and epigenomics involved in adipocyte differentiation and hypertrophy by multimodal nanoscopy.

The adipose tissue is the physiological energy reservoir for the whole body, but it also acts as a central metabolic organ in the regulation of body energy homeostasis. In particular, fat is stored in adipocytes inside cytosolic lipid droplets (LDs). Adipocyte hypertrophy occurring in obesity refers to an increase in adipocyte size due to LD enlargement. We aim to investigate the nuclear architecture and epigenetics during adipocyte differentiation and hypertrophy using an in vitro model of 3T3-L1 pre-adipocytes firstly differentiated into mature adipocytes, then cultured with fatty acids to induce hypertrophy. On pre-adipocytes, mature and hypertrophic adipocytes, we assessed lipid accumulation as a hypertrophy marker. Chromatin plays a central role in controlling gene expression under different physiological and pathological mechanisms. We employed optical nanoscale microscopy, such as confocal, super-resolution stimulation emission depletion (STED), and molecular biology analyses (ELISA), to assess the remodeling of nuclear architecture, chromatin organization, and epigenetic modifications associated with adipocyte differentiation and hypertrophy. Confocal and STED analyses showed appreciable differences in nuclear architecture, chromatin condensation, distribution, and chromatin methylation/acetylation among pre-adipocytes, mature and hypertrophic adipocytes. Moreover, we quantified the average changes in the DNA methylation (5-methylcytosine) by ELISA immunoassay. These preliminary results indicate epigenome and nuclear organization remodeling during adipocyte differentiation and hypertrophy. We can conclude that nuclear architecture remodeling is a significant and central factor in the genome function regulation.

Brain insulin signaling and cognition: Possible links.

Poor cognitive ability is a consequence of a wide variety of neurobehavioral disorders and is a growing health problem, especially among the elderly and patients with diabetes. The precise underlying cause of this complication is not well-defined. However, recent studies have highlighted the possible role of insulin hormone signaling in brain tissue. Insulin is a metabolic peptide integral to whole body energy homeostasis; it does, however, have extrametabolic impacts, such as upon neuronal circuits. Therefore, it has been suggested that insulin signaling may modify cognitive ability by yet unknown pathways. In the current review, we discuss the cognitive role of brain insulin signaling and consider the possible links between brain insulin signaling and cognitive ability.

Nutraceuticals in Brown Adipose Tissue Activation.

Obesity and its associated comorbidities have become pandemic, and challenge the global healthcare system. Lifestyle changes, nutritional interventions and phamaceuticals should be differently combined in a personalized strategy to tackle such a public health burden. Altered brown adipose tissue (BAT) function contributes to the pathophysiology of obesity and glucose metabolism dysfunctions. BAT thermogenic activity burns glucose and fatty acids to produce heat through uncoupled respiration, and can dissipate the excessive calorie intake, reduce glycemia and circulate fatty acids released from white adipose tissue. Thus, BAT activity is expected to contribute to whole body energy homeostasis and protect against obesity, diabetes and alterations in lipid profile. To date, pharmacological therapies aimed at activating brown fat have failed in clinical trials, due to cardiovascular side effects or scarce efficacy. On the other hand, several studies have identified plant-derived chemical compounds capable of stimulating BAT thermogenesis in animal models, suggesting the translational applications of dietary supplements to fight adipose tissue dysfunctions. This review describes several nutraceuticals with thermogenic properties and provides indications, at a molecular level, of the regulation of the adipocyte thermogenesis by the mentioned phytochemicals.

The proximal intestinal Fatty Acid-Binding Proteins liver FABP (LFABP) and intestinal FABP (IFABP) differentially modulate whole body energy homeostasis but are not centrally involved in net dietary lipid absorption: Studies of the LFABP/IFABP double knockout mouse

Proximal intestinal enterocytes expresses both intestinal-fatty acid binding protein (IFABP; FABP2) and liver-FABP (LFABP; FABP1). These FABPs are thought to be important in the net uptake of dietary lipid from the intestinal lumen, however their specific and potentially unique functions in the enterocyte remain incompletely understood. We previously showed markedly divergent phenotypes in LFABP−/− vs. IFABP−/− mice fed high-fat diets, with the former becoming obese and the latter remaining lean relative to wild-type (WT) mice, supporting different functional roles for each protein. Interestingly, neither mouse model displayed increased fecal lipid concentration, raising the question of whether the presence of one FABP was sufficient to compensate for absence of the other. Here, we generated an LFABP and IFABP double knockout mouse (DKO) to determine whether simultaneous ablation would lead to fat malabsorption, and to further interrogate the individual vs. overlapping functions of these proteins. Male WT, IFABP−/−, LFABP−/−, and DKO mice were fed a low-fat (10 % kcal) or high-fat (45 % kcal) diet for 12 weeks. The body weights and fat mass of the DKO mice integrated those of the LFABP−/− and IFABP−/− single knockouts, supporting the notion that IFABP and LFABP have distinct functions in intestinal lipid assimilation that result in downstream alterations in systemic energy metabolism. Remarkably, no differences in fecal fat concentrations were found in the DKO compared to WT, revealing that the FABPs are not required for net intestinal uptake of dietary lipid.

Hypothalamic effective connectivity at rest is associated with body weight and energy homeostasis.

Hunger and satiety drive eating behaviours via changes in brain function. The hypothalamus is a central component of the brain networks that regulate food intake. Animal research parsed the roles of the lateral hypothalamus (LH) and medial hypothalamus (MH) in hunger and satiety, respectively. Here, we examined how hunger and satiety change information flow between human LH and MH brain networks, and how these interactions are influenced by body mass index (BMI). Forty participants (16 overweight/obese) underwent two resting-state functional MRI scans while being fasted and sated. The excitatory/inhibitory influence of information flow between the MH and LH was modelled using spectral dynamic causal modelling. Our results revealed two core networks interacting across homeostatic state and weight: subcortical bidirectional connections between the LH, MH and the substantia nigra pars compacta (prSN), and cortical top-down inhibition from fronto-parietal and temporal areas. During fasting, we found higher inhibition between the LH and prSN, whereas the prSN received greater top-down inhibition from across the cortex. Individuals with higher BMI showed that these network dynamics occur irrespective of homeostatic state. Our findings reveal fasting affects brain dynamics over a distributed hypothalamic-midbrain-cortical network. This network is less sensitive to state-related fluctuations among people with obesity.