Control Of Energy Homeostasis Research Articles

Metabolome in Tibialis and Soleus Muscles in Wild-Type and Pin1 Knockout Mice through High-Resolution Magic Angle Spinning 1H Nuclear Magnetic Resonance Spectroscopy.

Skeletal muscles are heterogenous tissues composed of different myofiber types that can be classified as slow oxidative, fast oxidative, and fast glycolytic which are distinguished on the basis of their contractile and metabolic properties. Improving oxidative metabolism in skeletal muscles can prevent metabolic diseases and plays a protective role against muscle wasting in a number of neuromuscular diseases. Therefore, achieving a detailed understanding of the factors that regulate myofiber metabolic properties might provide new therapeutic opportunities for these diseases. Here, we investigated whether peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) is involved in the control of myofiber metabolic behaviors. Indeed, PIN1 controls glucose and lipid metabolism in a number of tissues, and it is also abundant in adult skeletal muscles; however, its role in the control of energy homeostasis in this tissue is still to be defined. To start clarifying this topic, we compared the metabolome of the tibialis anterior muscle (mainly glycolytic) and soleus muscle (oxidative) in wild-type and Pin1 knockout mice with High-Resolution Magic Angle Spinning (HR-MAS) NMR on intact tissues. Our analysis reveals a clear demarcation between the metabolomes in the two types of muscles and allows us to decode a signature able to discriminate the glycolytic versus oxidative muscle phenotype. We also detected some changes in Pin1-depleted muscles that suggest a role for PIN1 in regulating the metabolic phenotype of skeletal muscles.

Canonical transient receptor potential channels and hypothalamic control of homeostatic functions.

Recent molecular biological and electrophysiological studies have identified multiple transient receptor potential (TRP) channels in hypothalamic neurons as critical modulators of homeostatic functions. In particular, the canonical transient receptor potential channels (TRPCs) are expressed in hypothalamic neurons that are vital for the control of fertility and energy homeostasis. Classical neurotransmitters such as serotonin and glutamate and peptide neurotransmitters such as kisspeptin, neurokinin B and pituitary adenylyl cyclase-activating polypeptide signal through their cognate G protein-coupled receptors to activate TPRC 4, 5 channels, which are essentially ligand-gated calcium channels. In addition to neurotransmitters, circulating hormones like insulin and leptin signal through insulin receptor (InsR) and leptin receptor (LRb), respectively, to activate TRPC 5 channels in hypothalamic arcuate nucleus pro-opiomelanocortin (POMC) and kisspeptin (arcuate Kiss1 [Kiss1ARH]) neurons to have profound physiological (excitatory) effects. Besides its overt depolarizing effects, TRPC channels conduct calcium ions into the cytoplasm, which has a plethora of downstream effects. Moreover, not only the expression of Trpc5 mRNA but also the coupling of receptors to TRPC 5 channel opening are regulated in different physiological states. In particular, the mRNA expression of Trpc5 is highly regulated in kisspeptin neurons by circulating estrogens, which ultimately dictates the firing pattern of kisspeptin neurons. In obesity states, InsRs are "uncoupled" from opening TRPC 5 channels in POMC neurons, rendering them less excitable. Therefore, in this review, we will focus on the critical role of TRPC 5 channels in regulating the excitability of Kiss1ARH and POMC neurons in different physiological and pathological states.

Nav1.8-expressing neurons control daily oscillations of food intake, body weight and gut microbiota in mice.

Recent evidence suggests a role of sensory neurons expressing the sodium channel Nav1.8 on the energy homeostasis control. Using a murine diphtheria toxin ablation strategy and ad libitum and time-restricted feeding regimens of control or high-fat high-sugar diets, here we further explore the function of these neurons on food intake and on the regulation of gastrointestinal elements transmitting immune and nutrient sensing.The Nav1.8+ neuron ablation increases food intake in ad libitum and time-restricted feeding, and exacerbates daily body weight variations. Mice lacking Nav1.8+ neurons show impaired prandial regulation of gut hormone secretion and gut microbiota composition, and altered intestinal immunity.Our study demonstrates that Nav1.8+ neurons are required to control food intake and daily body weight changes, as well as to maintain physiological enteroendocrine and immune responses and the rhythmicity of thegut microbiota, which highlights the potential of Nav1.8+ neurons to restore energy balance in metabolic disorders.

MRAP2 Inhibits β-Arrestin-2 Recruitment to the Prokineticin Receptor 2.

Melanocortin receptor accessory protein 2 (MRAP2) is a membrane protein that binds multiple G protein-coupled receptors (GPCRs) involved in the control of energy homeostasis, including prokineticin receptors. These GPCRs are expressed both centrally and peripherally, and their endogenous ligands are prokineticin 1 (PK1) and prokineticin 2 (PK2). PKRs couple all G-protein subtypes, such as Gαq/11, Gαs, and Gαi, and recruit β-arrestins upon PK2 stimulation, although the interaction between PKR2 and β-arrestins does not trigger receptor internalisation. MRAP2 inhibits the anorexigenic effect of PK2 by binding PKR1 and PKR2. The aim of this work was to elucidate the role of MRAP2 in modulating PKR2-induced β-arrestin-2 recruitment and β-arrestin-mediated signalling. This study could allow the identification of new specific targets for potential new drugs useful for the treatment of the various pathologies correlated with prokineticin, in particular, obesity.

Establishment of a targeted analysis method for gangliosides in mouse tissues by HILIC-ESI-MS/MS.

Gangliosides play an imperative role in cell signaling, neuronal recovery, apoptosis, and other physiological processes. For example, GM3 can regulate hypothalamic leptin resistance and control energy homeostasis, GD3 can mediate cell proliferation and differentiation and induce apoptosis, and GQ1b can stimulate neurogenesis. Therefore, the present study sought to establish and optimize the targeted analysis method for ganglioside subclasses and their molecular species using hydrophilic interaction liquid chromatography-triple quadrupole-MS/MS (HILIC-QQQ-MS/MS). Additionally, the fragmentation pattern of different ganglioside subclasses and their retention time patterns were analyzed, providing more accurate qualitative results. The limit of quantitation (LOQ) was as low as 10-4ng. Moreover, the molecular species of gangliosides in the liver, cortex, and hypothalamus of C57BL/6 mice were analyzed using the established method. A total of 23 ganglioside subclasses with 164 molecular species, including 40 O-acetylated ganglioside molecular species and 28 NeuGc ganglioside molecular species, were identified using the semi-quantitative analysis method of anexternal standard curve corrected by an internal standard. In addition to NeuGc gangliosides, the contents of ganglioside subclasses were more abundant in the mouse brain than those in the mouse liver; especially, the contents of unsaturated gangliosides in the hypothalamus were much higher than those in the liver. Among them, O-acetylated gangliosides were detected only in the cortex and hypothalamus at a concentration of up to 100μg/mg protein (40 molecular species). Overall, the proposed method expanded the detectable number of ganglioside subclasses and molecular species in biological samples and provided more opportunities for further study of the biological functions of gangliosides.

PROTEIN ARGININE METHYLTRANSFERASE 1 REGULATES ADULT INTESTINAL CELL PROLIFERATION AND ENTEROENDOCRINE CELLS DIFFERENTIATION

Abstract The adult intestinal epithelium is a complex, self-renewing tissue composed of specialized cell types with diverse functions. Intestinal stem cells (ISCs) at the base of crypts divide and differentiate into absorptive and secretory cells. Enteroendocrine cells (EEC), one type of secretory cells, are the most abundant hormone-producing cells in mammals and involved in the control of energy homeostasis. Many studies investigated the mechanisms that control cell fate determination; however, regulation of EEC development and function are still unclear or controversial. Here, we found that Protein arginine methyltransferase 1(PRMT1), a major arginine methyltransferase, is highly expressed in the proliferating transit-amplifying (TA) cells and ISCs of adult mouse intestinal crypts. By using tamoxifen-induced intestinal epithelial cell-specific deletion of PRMT1 in adult mice, we observed the number of EEC dramatically increased. Transcription analyses showed the expression levels of Enteroendocrine-specific hormone and transcription factors are upregulated in PRMT1-deficient small intestine. In addition, the top enriched upregulated pathways were all associated with EEC functions. Concomitantly, Neurogenin 3-expressing progenitor cells accumulate in the mutant small intestine, and its target genes such as Neuod1, pax4, insm1 are upregulated of mutant crypts by RT-PCR. Furthermore, intestinal epithelium of the mutant mice showed elongated crypts in the small intestine, while increased cell proliferation in TA cells. Additionally, inducible PRMT1 deletion led to increased cell death, which compensated for increased cell proliferation in the crypts to maintain overall intestinal morphology and intestinal homeostasis. Together, our results revealed that the loss of PRMT1 in the adult intestinal epithelium altered TA cell proliferation and EEC differentiation, which was probably via Neurogenin 3-mediated pathway. Thus, our results may provide potential roles of PRMT1 as an essential transcriptional regulator of EECs specification and strategy for metabolic disorder.

The Ablation of Sensory Neurons Expressing the Nav1.8 Sodium Channel Improves Glucose Homeostasis and Amplifies the GLP-1 Signaling in Obese Female Mice.

Sensory neurons expressing the sodium channel Nav1.8 contain a repertoire of receptors for nutrient, hormonal, and inflammatory ligands. However, their function in key regulators of energy homeostasis control is not well understood and is completely unexplored in females. Mice lacking neurons expressing the sodium channel Nav1.8 were generated using an ablation strategy based on cre recombinase-mediated expression of diphtheria toxin fragment A (DTA) (Nav1.8-cre/DTA mice) to investigate whether these neurons modulate body weight, food intake, gut hormone secretion, gastrointestinal transit, and glucose tolerance in response to nutrient challenges in a sex-dependent manner. Male Nav1.8-cre/DTA mice show resistance to gain weight in response to high-fat high-sugar diet (HFHSD), whereas females lacking Nav1.8+ neurons have improved oral glucose tolerance accompanied by higher insulin levels and attenuated glucagon secretion after an oral glucose load. Female Nav1.8-cre/DTA mice also show higher fasting and postprandial glucagon like peptide-1 (GLP-1) levels with an increased number of GLP-1-positive cells. Finally, ablation of Nav1.8-expressing neurons accelerates the gastrointestinal transit in female mice under HFHSD. This data demonstrates sex-dependent differences in the Nav1.8-mediated regulation of energy metabolism, and provides new insights that may help in the design of sex-specific neuromodulation therapies for metabolic disorders induced by diets rich in fats and simple sugars.

CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice

Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C16:0 ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.

Metabolic consequences of skeletal muscle- and liver-specific BBSome deficiency.

The BBSome is a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins including BBS1. Humans and mice lacking a functional BBSome display obesity and type 2 diabetes, highlighting the importance of this protein complex for metabolic regulation. However, the contribution of the BBSome in insulin-sensitive tissues such as skeletal muscle and liver to metabolic regulation is ill-defined. Here, we show that disruption of the BBSome through Bbs1 gene deletion in the skeletal muscle had no effect on body weight or glucose handling, but improved insulin sensitivity of female mice without changing insulin receptor signaling. Interestingly, when fed an obesogenic diet, male mice lacking the Bbs1 gene in skeletal muscle exhibited heightened insulin sensitivity despite the comparable weight gain and glucose tolerance relative to controls. On the other hand, normal chow-fed mice missing the Bbs1 gene in hepatocytes displayed increased body weight, as well as impaired glucose handling and insulin sensitivity. This was associated with attenuated insulin signaling in liver and hepatocytes, but not skeletal muscle and white adipose tissue. Moreover, hepatocytes lacking the Bbs1 gene displayed significant reduction in plasma membrane insulin receptor levels due to the mitochondrial dysfunction evoked by loss of the BBSome. Together, these findings demonstrate that myocyte BBSome is minimally involved in metabolic regulation, whereas the hepatic BBSome plays a critical role in the control of energy homeostasis and insulin sensitivity through its requirement for insulin receptor trafficking.NEW & NOTEWORTHY The ongoing epidemic of obesity and associated illnesses highlights the need to understand the biological processes that regulate energy balance. Here, we identified an important role for a protein complex called BBSome in the control of hepatic function. We show that the liver BBSome is necessary to maintain body weight and blood glucose levels due to its requirements to generate energy and detect insulin, a hormone that is essential for metabolic regulation.

Visfatin in the porcine pituitary gland: expression and regulation of secretion during the oestrous cycle and early pregnancy

Visfatin is a multifunctional protein which, besides the control of energy homeostasis, seems to be also involved in the regulation of female fertility through the influence on the endocrine hypothalamus-pituitary-gonadal axis, including the pituitary. The aim of this study was to investigate the expression of visfatin mRNA and protein in the anterior (AP) and posterior pituitary lobes of the pig during the oestrous cycle and early pregnancy. In AP, we also examined colocalisation of visfatin with pituitary tropic hormones. Moreover, we aimed to evaluate the in vitro effects of GnRH, FSH, LH, and insulin on visfatin protein concentration and secretion in AP cells during the cycle. The study showed that visfatin is present in all types of porcine pituitary endocrine cells and its expression is reliant on stage of the cycle or pregnancy. GnRH, FSH, LH and insulin stimulated visfatin secretion by AP cells on days 17 to 19 of the cycle, while on days 2 to 3 visfatin release was enhanced only by LH. Summarising, visfatin is locally produced in the pituitary in a way dependent on hormonal milieu typical for reproductive status of pigs. Further research is required to clarify the role of visfatin in the pituitary gland.

Biohybrid tongue based on hypothalamic neuronal network-on-a-chip for real-time blood glucose sensing and assessment

The expression of sweet receptors in the hypothalamus has been implicated in energy homeostasis control and the pathogenesis of obesity and diabetes. However, the exact mechanism by which hypothalamic glucose-sensing neurons function remains unclear. Conventional detection methods, such as fiber photometry, optogenetics, brain-machine interfaces, patch clamp and calcium imaging, pose limitations for real-time glucose perception due to their complexity, cytotoxicity and so on. Therefore, this study proposes a biohybrid tongue based on hypothalamic neuronal network (HNN)-on-a-chip coupling with microelectrode array (MEA) for real-time glucose perception. Hypothalamic neuronal cultures were cultivated on a two-dimensional “brain-on-chip” device, enabling the formation of neuronal networks and electrophysiological signal detection. Additionally, we investigated the endogenous expression of sweet taste receptors (T1R2/T1R3) in hypothalamic neuronal cells, providing the basis for the biohybrid tongue based on HNN-on-a-chip's sweetness detection capabilities. The spike signal response to sucrose and glucose stimulation was detected, and concentration-dependent responses were explored with glucose concentrations ranging from 0.01 mM to 8 mM. MEAs allow for real-time recordings, enabling the observation of dynamic changes in neuronal responses to glucose fluctuations over time. The biohybrid tongue based on HNN-on-a-chip can measure various parameters, including spike frequency and amplitude, providing insights into neuronal firing patterns and excitability. Moreover, hypothalamic glucoregulatory neurons that sense and respond to changes in blood glucose was identified, including glucose-excited neurons (GE-Neurons) and glucose-inhibited neurons (GI-Neurons). The detection range for GE-Neurons spans from 0.4 to 6 mM, while GI-Neurons demonstrate sensitivity within the range of 1–8 mM. And the glucose detection limit was firmly established at 0.01 mM. Through non-linear regression analysis, the IC50 for GI-Neurons' spike firing was determined to be 4.18 mM. In conclusion, the biohybrid tongue based on HNN-on-a-chip offers a valuable in vitro tool for studying hypothalamic neurons, elucidating glucose sensing mechanisms, and understanding hypothalamic neuronal function.

Transcriptome analysis of ovarian tissues highlights genes controlling energy homeostasis and oxidative stress as potential drivers of heterosis for egg number and clutch size in crossbred laying hens

Heterosis is the major benefit of crossbreeding and has been exploited in laying hens breeding for a long time. This genetic phenomenon has been linked to various modes of nonadditive gene action. However, the molecular mechanism of heterosis for egg production in laying hens has not been fully elucidated. To fill this research gap, we sequenced mRNAs and lncRNAs of the ovary stroma containing prehierarchical follicles in White Leghorn, Rhode Island Red chickens as well as their reciprocal crossbreds that demonstrated heterosis for egg number and clutch size. We further delineated the modes of mRNAs and lncRNAs expression to identify their potential functions in the observed heterosis. Results showed that dominance was the principal mode of nonadditive expression exhibited by mRNAs and lncRNAs in the prehierarchical follicles of crossbred hens. Specifically, low-parent dominance was the main mode of mRNA expression, while high-parent dominance was the predominant mode of lncRNA expression. Important pathways enriched by genes that showed higher expression in crossbreds compared to either one or both parental lines were cell adhesion molecules, tyrosine and purine metabolism. In contrast, ECM-receptor interaction, focal adhesion, PPAR signaling, and ferroptosis were enriched in genes with lower expression in the crossbred. Protein network interaction identified nonadditively expressed genes including apolipoprotein B (APOB), transferrin, acyl-CoA synthetase medium-chain family member (APOBEC) 3, APOBEC1 complementation factor, and cathepsin S as hub genes. Among these potential hub genes, APOB was the only gene with underdominance expression common to the 2 reciprocal crossbred lines, and has been linked to oxidative stress. LncRNAs with nonadditive expression in the crossbred hens targeted natriuretic peptide receptor 1, epidermal differentiation protein beta, spermatogenesis-associated gene 22, sperm-associated antigen 16, melanocortin 2 receptor, dolichol kinase, glycine amiinotransferase, and prolactin releasing hormone receptor. In conclusion, genes with nonadditive expression in the crossbred may play crucial roles in follicle growth and atresia by improving follicle competence and increasing oxidative stress, respectively. These 2 phenomena could underpin heterosis for egg production in crossbred laying hens.

OVOL2: an epithelial lineage determiner with emerging roles in energy homeostasis.

Ovo like zinc finger 2 (OVOL2) is an evolutionarily conserved regulator of epithelial lineage determination and differentiation during embryogenesis. OVOL2 binds to DNA using zinc-finger domains to suppress epithelial-mesenchymal transition (EMT), which is critical for tumor metastasis. However, recent studies have suggested some noncanonical roles of OVOL2 that do not rely on the DNA binding of zinc-finger domains or regulation of EMT. OVOL2 and EMT regulators have emerging roles in adipogenesis, thermogenesis, and lipid metabolism. Here, we review different roles of OVOL2 from embryo development to adult tissue homeostasis, and discuss how OVOL2 and other EMT regulators orchestrate a regulatory network to control energy homeostasis. Last, we propose potential applications of targeting OVOL2 to reduce human obesity.

Transcriptomic Variation of Amphiprion Percula (Lacepède, 1802) in Response to Infection with Cryptocaryon Irritans Brown, 1951.

Cryptocaryon irritans (Brown 1951) frequently infect the Pomacentridae fishes causing severe economic losses. However, the anti-C. irritans' molecular mechanism in these fishes remains largely unknown. To address this issue, we conducted RNA-Seq for C. irrtians-infected gills of the clownfish Amphiprion percula (Lacepède 1802) at the early (day 1) and late (day 3) stages of infection. A total of 1655 differentially expressed genes (DEGs) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs showed a vast genetic variation related to the following aspects: ECM-receptor interaction, P13K-Akt signalling, cytokine-cytokine receptor interaction, and endocytosis. During the early phase of infection, key genes involved in ATP production, energy homeostasis, and stress control were abruptly increased. In the late phase, however, acute response molecules of the peripheral nervous system (synaptic transmission and local immunity), metabolic system triggering glycogen synthesis, energy maintenance, and osmoregulation were found to be critical. The highest number of upregulated genes (URGs) recovered during the early phase was included under the 'biological process' category, which primarily functions as response to stimuli, signalling, and biological regulation. In the late phase, most of the URGs were related to gene regulation and immune system processes under 'molecular function' category. The immune-related URGs of early infection include major histocompatibility complex (MHC) class-II molecules apparently triggering CD4+ T-cell-activated Th responses, and that of late infection include MHC class-1 molecules for the possible culmination of CD8+ T-cell triggered cytotoxicity. The high level of genic single nucleotide polymorphisms (SNPs) identified during the late phase of infection is likely to influence their susceptibility to secondary infection. In summary, the identified DEGs and their related metabolic and immune-related pathways and the SNPs may provide new insights into coordinating the immunological events and improving resistance in Pomacentridae fishes against C. irritans.

Drastic decline in vasoactive intestinal peptide expression in the suprachiasmatic nucleus in obese mice on a long-term high-fat diet

The suprachiasmatic nucleus (SCN) is the main region for the regulation of circadian rhythms. Although the SCN contains a heterogeneous neurochemical phenotype with a wide variety of neuropeptides, a key role has been suggested for the vasoactive intestinal neuropeptide (VIP) as a modulator circadian, reproductive, and seasonal rhythms. VIP is a 28-amino acid polypeptide hormone that belongs to the secretin-glucagon peptide superfamily and shares 68 % homology with the pituitary adenylate cyclase-activating polypeptide (PACAP). VIP acts as an endogenous appetite inhibitor in the central nervous system, where it participates in the control of appetite and energy homeostasis. In recent years, significant efforts have been made to better understand the role of VIP in the regulation of appetite/satiety and energy balance. This study aimed to elucidate the long-term effect of an obesogenic diet on the distribution and expression pattern of VIP in the SCN and nucleus accumbens (NAc) of C57BL/6 mice. A total of 15 female C57BL/6J mice were used in this study. Female mice were fed ad libitum with water and, either a standard diet (SD) or a high-fat diet (HFD) to induce obesity. There were 7 female mice on the SD and 8 on the HFD. The duration of the experiment was 365 days. The morphological study was performed using immunohistochemistry and double immunofluorescence techniques to study the neurochemical profile of VIP neurons of the SCN of C57BL/6 mice. Our data show that HFD-fed mice gained weight and showed reduced VIP expression in neurons of the SCN and also in fibres located in the NAc. Moreover, we observed a loss of neuropeptide Y (NPY) expression in fibres surrounding the SCN. Our findings on VIP may contribute to the understanding of the pathophysiological mechanisms underlying obesity in regions associated with uncontrolled intake of high-fat foods and the reward system, thus facilitating the identification of novel therapeutic targets.

Fasting increases circulating angiotensin levels and brain Agtr1a expression in male rats.

In addition to being recognised for involvement in cardiovascular control and hydromineral balance, the renin-angiotensin system (RAS) has also been associated with the neuroendocrine control of energy balance. One of the main brain sites for angiotensin II (ANG II)/type 1 receptor (AT1 R) signalling is the subfornical organ (SFO), a circumventricular organ related to the control of autonomic functions, motivated behaviours and energy metabolism. Thus, we hypothesised that circulating ANG II may act on the SFO AT1 R receptors to integrate metabolic and hydromineral balance. We evaluated whether food deprivation can modulate systemic RAS activity and Agrt1a brain expression, and if ANG II/AT1 R signalling influences the hypothalamic expression of mRNAs encoding neuropeptides and food and water ingestion in fed and fasted Wistar rats. We found a significant increase in both ANG I and ANG II plasma levels after 24 and 48 h of fasting. Expression of Agrt1a mRNA in the SFO and paraventricular nucleus (PVN) also increased after food deprivation for 48 h. Treatment of fasted rats with low doses of losartan in drinking water attenuated the decrease in glycemia and meal-associated water intake without changing the expression in PVN or arcuate nucleus of mRNAs encoding selected neuropeptides related to energy homeostasis control. These findings point to a possible role of peripheral ANG II/SFO-AT1 R signalling in the control of refeeding-induced thirst. On the other hand, intracerebroventricular losartan treatment decreased food and water intake over dark time in fed but not in fasted rats.

MicroRNA-22 Is a Key Regulator of Lipid and Metabolic Homeostasis.

Obesity is a growing public health problem associated with increased risk of type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD) and cancer. Here, we identify microRNA-22 (miR-22) as an essential rheostat involved in the control of lipid and energy homeostasis as well as the onset and maintenance of obesity. We demonstrate through knockout and transgenic mouse models that miR-22 loss-of-function protects against obesity and hepatic steatosis, while its overexpression promotes both phenotypes even when mice are fed a regular chow diet. Mechanistically, we show that miR-22 controls multiple pathways related to lipid biogenesis and differentiation. Importantly, genetic ablation of miR-22 favors metabolic rewiring towards higher energy expenditure and browning of white adipose tissue, suggesting that modulation of miR-22 could represent a viable therapeutic strategy for treatment of obesity and other metabolic disorders.

Altered function of arcuate leptin receptor expressing neuropeptide Y neurons depending on energy balance

ObjectiveOne of leptin's main targets in the hypothalamus are neuropeptide Y (NPY) neurons, with selective deletion of leptin receptors (Lepr) specifically in Npy neurons resulting in major alterations of energy partitioning between fat and bone mass. However, the specific action of these Npy+/Lepr+ neurons compared to Npy-negative Lepr (Npy−/Lepr+) neurons in regard to energy homeostasis regulation is unknown. MethodsSpecific AAV viral vectors were generated using DREADD and INTRSECT technology and used in male LeprCre/+ and LeprCre/+;NpyFlp/+ mice to assess the effect of activating either all Lepr neurons or specifically Npy+/Lepr+ or Npy−/Lepr+ neurons only on feeding, energy homeostasis control, and body composition. ResultsSelective stimulation of Npy+/Lepr+ neurons led to an immediate decrease in respiratory quotient followed by a delayed increase in food intake in standard chow fed, but interestingly not in high fat diet (HFD) fed mice. In addition, stimulation of Npy+/Lepr+ neurons led to a robust increase in brown adipose tissue thermogenesis and improved glucose tolerance. These effects were not observed in standard chow fed mice when Npy−/Lepr+ expressing neurons were specifically activated, suggesting the effects of leptin on these parameters are driven by NPY. However, under HFD condition when leptin levels are elevated, the stimulation of the Npy−/Lepr+ neurons increased food intake, physical activity and energy expenditure. Interestingly, chronic stimulation of Npy-positive Lepr neurons was able to increase bone mass independently of bodyweight, whilst chronic stimulation of the Npy−/Lepr+ neurons resulted in increased bodyweight and fat mass with proportionate increases in bone mass. ConclusionsTogether, these data indicate that leptin signalling through Npy-positive Lepr-expressing neurons controls energy partitioning via stimulation of thermogenesis, energy expenditure, and the use of fat as a fuel source. However, under prolonged HFD, leptin resistance may occur and actions of leptin signalling through Npy-negative Lepr hypothalamic neurons may exacerbate excess food intake.

IFI27 Integrates Succinate and Fatty Acid Oxidation to Promote Adipocyte Thermogenic Adaption.

Mitochondria are the pivot organelles to control metabolism and energy homeostasis. The capacity of mitochondrial metabolic adaptions to cold stress is essential for adipocyte thermogenesis. How brown adipocytes keep mitochondrial fitness upon a challenge of cold-induced oxidative stress has not been well characterized. This manuscript shows that IFI27 plays an important role in cristae morphogenesis, keeping intact succinate dehydrogenase (SDH) function and active fatty acid oxidation to sustain thermogenesis in brown adipocytes. IFI27 protein interaction map identifies SDHB and HADHA as its binding partners. IFI27 physically links SDHB to chaperone TNF receptor associated protein 1 (TRAP1), which shields SDHB from oxidative damage-triggered degradation. Moreover, IFI27 increases hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) catalytic activity in β-oxidation pathway. The reduced SDH level and fatty acid oxidation in Ifi27-knockout brown fat results in impaired oxygen consumption and defective thermogenesis. Thus, IFI27 is a novel regulator of mitochondrial metabolism and thermogenesis.

The Drosophila tumor necrosis factor receptor, Wengen, couples energy expenditure with gut immunity.

It is well established that tumor necrosis factor (TNF) plays an instrumental role in orchestrating the metabolic disorders associated with late stages of cancers. However, it is not clear whether TNF/TNF receptor (TNFR) signaling controls energy homeostasis in healthy individuals. Here, we show that the highly conserved Drosophila TNFR, Wengen (Wgn), is required in the enterocytes (ECs) of the adult gut to restrict lipid catabolism, suppress immune activity, and maintain tissue homeostasis. Wgn limits autophagy-dependent lipolysis by restricting cytoplasmic levels of the TNFR effector, TNFR-associated factor 3 (dTRAF3), while it suppresses immune processes through inhibition of the dTAK1/TAK1-Relish/NF-κB pathway in a dTRAF2-dependent manner. Knocking down dTRAF3 or overexpressing dTRAF2 is sufficient to suppress infection-induced lipid depletion and immune activation, respectively, showing that Wgn/TNFR functions as an intersection between metabolism and immunity allowing pathogen-induced metabolic reprogramming to fuel the energetically costly task of combatting an infection.