Beyond Host Defense: Emerging Functions of the Immune System in Regulating Complex Tissue Physiology.

The essential roles played by the immune system in the discrimination between self- versus non/altered-self and its integral role in promoting host defense against invading microbes and tumors have been extensively studied for many years. In these contexts, significant advances have been made in defining the molecular and cellular networks that orchestrate cell-cell communication to mediate host defense and pathogen expulsion. Notably, recent studies indicate that in addition to these classical immune functions, cells of the innate and adaptive immune system also sense complex tissue- and environment-derived signals, including those from the nervous system and the diet. In turn these responses regulate physiologic processes in multiple tissues throughout the body, including nervous system function, metabolic state, thermogenesis, and tissue repair. In this review we propose an integrated view of how the mammalian immune system senses and interacts with other complex organ systems to maintain tissue and whole-body homeostasis.

A mitochondrial EglN1-AMPKα axis drives breast cancer progression by enhancing metabolic adaptation to hypoxic stress.

Mitochondria play essential roles in cancer cell adaptation to hypoxia, but the underlying mechanisms remain elusive. Through mitochondrial proteomic profiling, we here find that the prolyl hydroxylase EglN1 (PHD2) accumulates on mitochondria under hypoxia. EglN1 substrate-binding region in the ß2ß3 loop is responsible for its mitochondrial translocation and contributes to breast tumor growth. Furthermore, we identify AMP-activated protein kinase alpha (AMPKα) as an EglN1 substrate on mitochondria. The EglN1-AMPKα interaction is essential for their mutual mitochondrial translocation. After EglN1 prolyl-hydroxylates AMPKα under normoxia, they rapidly dissociate following prolyl-hydroxylation, leading to their immediate release from mitochondria. In contrast, hypoxia results in constant EglN1-AMPKα interaction and their accumulation on mitochondria, leading to the formation of a Ca2+ /calmodulin-dependent protein kinase 2 (CaMKK2)-EglN1-AMPKα complex to activate AMPKα phosphorylation, ensuring metabolic homeostasis and breast tumor growth. Our findings identify EglN1 as an oxygen-sensitive metabolic checkpoint signaling hypoxic stress to mitochondria through its ß2ß3 loop region, suggesting a potential therapeutic target for breast cancer.

Mechanisms controlling metabolite concentrations of the Calvin Benson Cycle.

Maintaining proper metabolite levels in a complex metabolic network is crucial for maintaining a high flux through the network. In this paper, we discuss major regulatory mechanisms over the Calvin Benson Cycle (CBC) with regard to their roles in conferring homeostasis of metabolite levels in CBC. These include: 1) Redox regulation of enzymes in the CBC on one hand ensures that metabolite levels stay above certain lower bounds under low light while on the other hand increases the flux through the CBC under high light. 2) Metabolite regulations, especially allosteric regulations of major regulatory enzymes, ensure the rapid up-regulation of fluxes to ensure sufficient amount of triose phosphate is available for end product synthesis and concurrently avoid phosphate limitation. 3) A balanced activities of enzymes in the CBC help maintain balanced flux through CBC; some innate product feedback mechanisms, in particular the ADP feedback regulation of GAPDH and F6P feedback regulation of FBPase, exist in CBC to achieve such a balanced enzyme activities and hence flux distribution in the CBC for greater photosynthetic efficiency. Transcriptional regulation and natural variations of enzymes controlling CBC metabolite homeostasis should be further explored to maximize the potential of engineering CBC for greater efficiency.

Metabolic homeostasis and growth in abiotic cells.

Metabolism constitutes the core chemistry of life. How it began on the early Earth and whether it had a cellular origin are still uncertain. A leading hypothesis for life's origins postulates that metabolism arose from geochemical CO2-fixing pathways, driven by inorganic catalysts and energy sources, long before enzymes or genes existed. The acetyl-CoA pathway and the reductive tricarboxylic acid cycle are considered ancient reaction networks that hold relics of early carbon-fixing pathways. Although transition metals can promote many steps of these pathways, whether they form a functional metabolic network in abiotic cells has not been demonstrated. Here, we formulate a nonenzymatic carbon-fixing network from these pathways and determine its functional feasibility in abiotic cells by imposing fundamental physicochemical constraints. Using first principles, we show that abiotic cells can sustain a steady carbon-fixing cycle that performs a systemic function over a relatively narrow range of conditions. Furthermore, we find that in all feasible steady states, the operation of the cycle elevates the osmotic pressure, leading to volume expansion. These results suggest that achieving homeostatic metabolic states under prebiotic conditions was possible, but challenging, and volume growth was a fundamental property of early metabolism.

Immune cell cholinergic signaling in adipose thermoregulation and immunometabolism.

Research focusing on adipose immunometabolism has been expanded from inflammation in white fat during obesity development to immune cell function regulating thermogenic fat, energy expenditure, and systemic metabolism. This opinion discusses our current understanding of how resident immune cells within the thermogenic fat niche may regulate whole-body energy homeostasis. Furthermore, various types of immune cells can synthesize acetylcholine (ACh) and regulate important physiological functions. We highlight a unique subset of cholinergic macrophages within subcutaneous adipose tissue, termed cholinergic adipose macrophages (ChAMs); these macrophages interact with beige adipocytes through cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) signaling to induce adaptive thermogenesis. We posit that these newly identified thermoregulatory macrophages may broaden our view of immune system functions for maintaining metabolic homeostasis and potentially treating obesity and metabolic disorders.

mTOR in metabolic homeostasis and disease.

The ability to maintain cellular metabolic homeostasis is critical to life, in which mTOR plays an important role. This kinase integrates upstream nutrient signals and performs essential functions in physiology and metabolism by increasing metabolism and suppressing autophagy. Thus, dysregulation of mTOR activity leads to diseases, especially metabolic diseases such as cancer, type 2 diabetes and neurological disorders. Therefore, inhibition of overactivated mTOR becomes a rational approach to treat a variety of metabolic diseases. In this review, we discuss how mTOR responds to upstream signals and how mTOR regulates metabolic processes, including protein, nucleic acid, and lipid metabolism. Furthermore, we discuss the possible causes and consequences of dysregulated mTOR signaling activity, and summarize relevant applications, such as inhibition of mTOR activity to treat these diseases. This review will advance our comprehensive knowledge of the association between mTOR and metabolic homeostasis, which has significant ramifications for human health.

Glucose controls manganese homeostasis through transcription factors regulating known and newly identified manganese transporter genes in Bacillus subtilis.

Mn2+ is an essential nutrient whose concentration is tightly controlled in bacteria. In Bacillus subtilis, the Mn2+-activated transcription factor MntR controls Mn2+ transporter genes. However, factors regulating intracellular Mn2+ concentration are incompletely understood. Here, we found that glucose addition induces an increase in intracellular Mn2+ concentration. We determined this upshift was mediated by glucose induction of the major Mn2+ importer gene mntH by the transcription factor AhrC, which is known to be involved in arginine metabolism and to be indirectly induced by glucose. In addition, we identified novel AhrC-regulated genes encoding the Mn2+ importer YcsG and the ABC-type exporter YknUV. We found the expression of these genes was also regulated by glucose and contributes to the glucose induction of Mn2+ concentrations. ycsG expression is regulated by MntR as well. Furthermore, we analyzed the interaction of AhrC and MntR with the promoter driving ycsG expression and examined the Mn2+-dependent induction of this promoter to identify the transcription factors responsible for the Mn2+ induction. RNA-Seq revealed that disruption of ahrC and mntR affected the expression of 502 and 478 genes, respectively (false discovery rate, <0.001, log2[fold change] ≥ |2|. The AhrC- and/or MntR-dependent expression of twenty promoters was confirmed by LacZ analysis, and AhrC or MntR binding to some of these promoters was observed via EMSA. The finding that glucose promotes an increase in intracellular Mn2+ levels without changes in extracellular Mn2+ concentrations is reasonable for the bacterium, as intracellular Mn2+ is required for enzymes and pathways mediating glucose metabolism.

Reversible expansion of tissue macrophages in response to macrophage colony-stimulating factor (CSF1) transforms systemic lipid and carbohydrate metabolism.

Macrophages regulate metabolic homeostasis in health and disease. Macrophage colony-stimulating factor (CSF1)-dependent macrophages contribute to homeostatic control of the size of the liver. This study aimed to determine the systemic metabolic consequences of elevating circulating CSF1. Acute administration of a CSF1-Fc fusion protein to mice led to monocytosis, increased resident tissue macrophages in the liver and all major organs, and liver growth. These effects were associated with increased hepatic glucose uptake and extensive mobilization of body fat. The impacts of CSF1 on macrophage abundance, liver size, and body composition were rapidly reversed to restore homeostasis. The effects of CSF1 on metabolism were independent of several known endocrine regulators and did not impact the physiological fasting response. Analysis using implantable telemetry in metabolic cages revealed progressively reduced body temperature and physical activity with no change in diurnal food intake. These results demonstrate the existence of a dynamic equilibrium between CSF1, the mononuclear phagocyte system, and control of liver-to-body weight ratio, which in turn controls systemic metabolic homeostasis. This novel macrophage regulatory axis has the potential to promote fat mobilization, without changes in appetence, which may have novel implications for managing metabolic syndrome.NEW & NOTEWORTHY CSF1 administration expands tissue macrophages, which transforms systemic metabolism. CSF1 drives fat mobilization and glucose uptake to support liver growth. The effects of CSF1 are independent of normal hormonal metabolic regulation. The effects of CSF1 are rapidly reversible, restoring homeostatic body composition. CSF1-dependent macrophages and liver size are coupled in a dynamic equilibrium.

Enhanced catabolism of glycine betaine and derivatives provides improved osmotic stress protection in Methylorubrum extorquens PA1.

Integration of metabolites into the overall metabolic network of a cell requires careful coordination dependent upon the ultimate usage of the metabolite. Different stoichiometric needs, and thus pathway fluxes, must exist for compounds destined for diverse uses, such as carbon sources, nitrogen sources, or stress-protective agents. Herein, we expand upon our previous work that highlighted the nature of glycine betaine (GB) metabolism in Methylobacteria to examine the utilization of GB-derivative compounds dimethylglycine (DMG) and sarcosine into Methylorubrum extorquens in different metabolic capacities, including as sole nitrogen and/or carbon sources. We isolated gain-of-function mutations that allowed M. extorquens PA1 to utilize dimethylglycine as a carbon source and dimethylglycine and sarcosine as nitrogen source. Characterization of mutants demonstrated selection for variants of the AraC-like regulator Mext_3735 that confer constitutive expression of the GB metabolic gene cluster, allowing direct utilization of the downstream GB derivatives. Finally, among the distinct isolates examined, we found that catabolism of the osmoprotectant used for selection (GB or dimethylglycine) enhanced osmotic stress resistance provided in the presence of that particular osmolyte. Thus, access to the carbon and nitrogen and osmoprotective effects of GB and DMG are made readily accessible through adaptive mutations. In M. extorquens PA1, the limitations to exploiting this group of compounds appear to exist predominantly at the levels of gene regulation and functional activity, rather than being constrained by transport or toxicity.IMPORTANCEOsmotic stress is a common challenge for bacteria colonizing the phyllosphere, where glycine betaine (GB) can be found as a prevalent osmoprotectant. Though Methylorubrum extorquens PA1 cannot use GB or its demethylation products, dimethylglycine (DMG) and sarcosine, as a sole carbon source, utilization is highly selectable via single nucleotide changes for both GB and DMG growth. The innate inability to use these compounds is due to limited flux through steps in the pathway and regulatory constraints. Herein, the characterization of the transcriptional regulator, Mext_3735 (GbdR), expands our understanding of the various roles in which GB derivatives can be used in M. extorquens PA1. Interestingly, increased catabolism of GB and derivatives does not interfere with, but rather improves, the ability of cells to thrive under increased salt stress conditions, suggesting that metabolic flux improves stress tolerance rather than providing a distinct tension between uses.

Engineering microbial metabolic homeostasis for chemicals production.

Microbial-based bio-refining promotes the development of a biotechnology revolution to encounter and tackle the enormous challenges in petroleum-based chemical production by biomanufacturing, biocomputing, and biosensing. Nevertheless, microbial metabolic homeostasis is often incompatible with the efficient synthesis of bioproducts mainly due to: inefficient metabolic flow, robust central metabolism, sophisticated metabolic network, and inevitable environmental perturbation. Therefore, this review systematically summarizes how to optimize microbial metabolic homeostasis by strengthening metabolic flux for improving biotransformation turnover, redirecting metabolic direction for rewiring bypass pathway, and reprogramming metabolic network for boosting substrate utilization. Future directions are also proposed for providing constructive guidance on the development of industrial biotechnology.

Impact of Plant-Based Dietary Fibers on Metabolic Homeostasis in High-Fat Diet Mice via Alterations in the Gut Microbiota and Metabolites.

BACKGROUND: The gut microbiota contributes to metabolic disease, and diet shapes the gut microbiota, emphasizing the need to better understand how diet impacts metabolic disease via gut microbiota alterations. Fiber intake is linked with improvements in metabolic homeostasis in rodents and humans, which is associated with changes in the gut microbiota. However, dietary fiber is extremely heterogeneous, and it is imperative to comprehensively analyze the impact of various plant-based fibers on metabolic homeostasis in an identical setting and compare the impact of alterations in the gut microbiota and bacterially derived metabolites from different fiber sources. OBJECTIVES: The objective of this study was to analyze the impact of different plant-based fibers (pectin, ß-glucan, wheat dextrin, resistant starch, and cellulose as a control) on metabolic homeostasis through alterations in the gut microbiota and its metabolites in high-fat diet (HFD)-fed mice. METHODS: HFD-fed mice were supplemented with 5 different fiber types (pectin, ß-glucan, wheat dextrin, resistant starch, or cellulose as a control) at 10% (wt/wt) for 18 wk (n = 12/group), measuring body weight, adiposity, indirect calorimetry, glucose tolerance, and the gut microbiota and metabolites. RESULTS: Only ß-glucan supplementation during HFD-feeding decreased adiposity and body weight gain and improved glucose tolerance compared with HFD-cellulose, whereas all other fibers had no effect. This was associated with increased energy expenditure and locomotor activity in mice compared with HFD-cellulose. All fibers supplemented into an HFD uniquely shifted the intestinal microbiota and cecal short-chain fatty acids; however, only ß-glucan supplementation increased cecal butyrate concentrations. Lastly, all fibers altered the small-intestinal microbiota and portal bile acid composition. CONCLUSIONS: These findings demonstrate that ß-glucan consumption is a promising dietary strategy for metabolic disease, possibly via increased energy expenditure through alterations in the gut microbiota and bacterial metabolites in mice.

Maternal secretin ameliorates obesity by promoting white adipose tissue browning in offspring.

Our knowledge of the coordination of intergenerational inheritance and offspring metabolic reprogramming by gastrointestinal endocrine factors is largely unknown. Here, we showed that secretin (SCT), a brain-gut peptide, is downregulated by overnutrition in pregnant mice and women. More importantly, genetic loss of SCT in the maternal gut results in undesirable phenotypes developed in offspring including enhanced high-fat diet (HFD)-induced obesity and attenuated browning of inguinal white adipose tissue (iWAT). Mechanistically, loss of maternal SCT represses iWAT browning in offspring by a global change in genome methylation pattern through upregulation of DNMT1. SCT functions to facilitate ubiquitination and degradation of DNMT1 by activating AMPKα, which contributes to the observed alteration of DNMT1 in progeny. Lastly, we showed that SCT treatment during pregnancy can reduce the development of obesity and improve glucose tolerance and insulin resistance in offspring of HFD-fed females, suggesting that SCT may serve as a novel biomarker or a strategy for preventing metabolic diseases.

The contribution of small heterodimer partner to the occurrence and progression of cholestatic liver injury.

BACKGROUND AND AIM: Small heterodimer partner (SHP, encoded by NR0B2) plays an important role in maintaining bile acid homeostasis. The loss of the hepatic farnesoid X receptor (FXR)/SHP signal can cause severe cholestatic liver injury (CLI). FXR and SHP have overlapping and nonoverlapping functions in bile acid homeostasis. However, the key role played by SHP in CLI is unclear. METHODS: In this study, an alpha-naphthylisothiocyanate (ANIT)-induced cholestasis mouse model was established. The effect of SHP knockout (SHP-KO) on liver and ileal pathology was evaluated. 16S rRNA gene sequencing analysis combined with untargeted metabolomics was applied to reveal the involvement of SHP in the pathogenesis of CLI. RESULTS: The results showed that ANIT (75 mg/kg) induced cholestasis in WT mice. No significant morphological changes were found in the liver and ileal tissue of SHP-KO mice. However, the serum metabolism and intestinal flora characteristics were significantly changed. Moreover, compared with the WT + ANIT group, the serum levels of ALT and AST in the SHP-KO + ANIT group were significantly increased, and punctate necrosis in the liver tissue was more obvious. The ileum villi showed obvious shedding, thinning, and shortening. In addition, SHP-KO-associated differential intestinal flora and differential biomarkers were significantly associated. CONCLUSION: In this study, we elucidated the serum metabolic characteristics and intestinal flora changes related to the aggravation of CLI in SHP-KO mice induced by ANIT.

Perturbations in plant energy homeostasis prime lateral root initiation via SnRK1-bZIP63-ARF19 signaling.

Plants adjust their energy metabolism to continuous environmental fluctuations, resulting in a tremendous plasticity in their architecture. The regulatory circuits involved, however, remain largely unresolved. In Arabidopsis, moderate perturbations in photosynthetic activity, administered by short-term low light exposure or unexpected darkness, lead to increased lateral root (LR) initiation. Consistent with expression of low-energy markers, these treatments alter energy homeostasis and reduce sugar availability in roots. Here, we demonstrate that the LR response requires the metabolic stress sensor kinase Snf1-RELATED-KINASE1 (SnRK1), which phosphorylates the transcription factor BASIC LEUCINE ZIPPER63 (bZIP63) that directly binds and activates the promoter of AUXIN RESPONSE FACTOR19 (ARF19), a key regulator of LR initiation. Consistently, starvation-induced ARF19 transcription is impaired in bzip63 mutants. This study highlights a positive developmental function of SnRK1. During energy limitation, LRs are initiated and primed for outgrowth upon recovery. Hence, this study provides mechanistic insights into how energy shapes the agronomically important root system.

Pharmacological Activities, Therapeutic Effects, and Mechanistic Actions of Trigonelline.

Trigonelline (TRG) is a natural polar hydrophilic alkaloid that is found in many plants such as green coffee beans and fenugreek seeds. TRG potentially acts on multiple molecular targets, including nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor γ, glycogen synthase kinase, tyrosinase, nerve growth factor, estrogen receptor, amyloid-ß peptide, and several neurotransmitter receptors. In this review, we systematically summarize the pharmacological activities, medicinal properties, and mechanistic actions of TRG as a potential therapeutic agent. Mechanistically, TRG can facilitate the maintenance and restoration of the metabolic homeostasis of glucose and lipids. It can counteract inflammatory constituents at multiple levels by hampering pro-inflammatory factor release, alleviating inflammatory propagation, and attenuating tissue injury. It concurrently modulates oxidative stress by the blockage of the detrimental Nrf2 pathway when autophagy is impaired. Therefore, it exerts diverse therapeutic effects on a variety of pathological conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional effects, including neuroprotection from neurodegenerative disorders and diabetic peripheral neuropathy, neuromodulation, mitigation of cardiovascular disorders, skin diseases, diabetic mellitus, liver and kidney injuries, and anti-pathogen and anti-tumor activities. Further validations are required to define its specific targeting molecules, dissect the underlying mechanistic networks, and corroborate its efficacy in clinical trials.

Multi-stress resilience in plants recovering from submergence.

Submergence limits plants' access to oxygen and light, causing massive changes in metabolism; after submergence, plants experience additional stresses, including reoxygenation, dehydration, photoinhibition and accelerated senescence. Plant responses to waterlogging and partial or complete submergence have been well studied, but our understanding of plant responses during post-submergence recovery remains limited. During post-submergence recovery, whether a plant can repair the damage caused by submergence and reoxygenation and re-activate key processes to continue to grow, determines whether the plant survives. Here, we summarize the challenges plants face when recovering from submergence, primarily focusing on studies of Arabidopsis thaliana and rice (Oryza sativa). We also highlight recent progress in elucidating the interplay among various regulatory pathways, compare post-hypoxia reoxygenation between plants and animals and provide new perspectives for future studies.

Ramadan intermittent fasting reduces visceral fat and improves gastrointestinal motility.

BACKGROUND: Ramadan is a model of intermittent fasting linked with possible beneficial effects. Scarce information, however, is available about the combined effects of Ramadan intermittent fasting (RIF) on anthropometric and metabolic indices, gastrointestinal symptoms, and motility. METHODS: In 21 healthy Muslims, we assessed the impact of RIF on caloric intake, physical activity, gastrointestinal symptoms and motility (gastric/gallbladder emptying by ultrasonography, orocaecal transit time by lactulose breath test), anthropometric indices, subcutaneous and visceral fat thickness (ultrasonography), glucose and lipid homeostasis. RESULTS: Mean caloric intake decreased from a median of 2069 kcal (range 1677-2641) before Ramadan to 1798 kcal (1289-3126) during Ramadan and increased again to 2000 kcal (1309-3485) after Ramadan. Although physical activity remained stable before, during, and after RIF, body weight, body mass index and waist circumference decreased in all subjects and in both genders, together with a significant decrease in subcutaneous and visceral fat thickness and insulin resistance. The postprandial gastric emptying speed was significantly faster after than before RIF. Fasting gallbladder volume was about 6% smaller after, than before Ramadan, with a stronger and faster postprandial gallbladder contraction. After RIF, lactulose breath test documented increased microbiota carbohydrate fermentation (postprandial H2 peak), and faster orocaecal transit time. RIF also significantly improved gastric fullness, epigastric pain and heartburn. CONCLUSIONS: RIF generates, in healthy subjects, multiple systemic beneficial effects in terms of fat burden, metabolic profile, gastrointestinal motility and symptoms. Further comprehensive studies should assess the potential beneficial effects of RIF in diseased people.

Impact of NAD+ metabolism on ovarian aging.

Nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme in cellular redox reactions, is closely associated with age-related functional degeneration and metabolic diseases. NAD exerts direct and indirect influences on many crucial cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cellular senescence, and immune cell functionality. These cellular processes and functions are essential for maintaining tissue and metabolic homeostasis, as well as healthy aging. Causality has been elucidated between a decline in NAD levels and multiple age-related diseases, which has been confirmed by various strategies aimed at increasing NAD levels in the preclinical setting. Ovarian aging is recognized as a natural process characterized by a decline in follicle number and function, resulting in decreased estrogen production and menopause. In this regard, it is necessary to address the many factors involved in this complicated procedure, which could improve fertility in women of advanced maternal age. Concerning the decrease in NAD+ levels as ovarian aging progresses, promising and exciting results are presented for strategies using NAD+ precursors to promote NAD+ biosynthesis, which could substantially improve oocyte quality and alleviate ovarian aging. Hence, to acquire further insights into NAD+ metabolism and biology, this review aims to probe the factors affecting ovarian aging, the characteristics of NAD+ precursors, and the current research status of NAD+ supplementation in ovarian aging. Specifically, by gaining a comprehensive understanding of these aspects, we are optimistic about the prominent progress that will be made in both research and therapy related to ovarian aging.

OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance.

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensing O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase in O-GlcNAc signaling in macrophages. O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. Suppressing O-GlcNAc signaling by O-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1) O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage O-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.

NGF and Its Role in Immunoendocrine Communication during Metabolic Syndrome.

Nerve growth factor (NGF) was the first neurotrophin described. This neurotrophin contributes to organogenesis by promoting sensory innervation and angiogenesis in the endocrine and immune systems. Neuronal and non-neuronal cells produce and secrete NGF, and several cell types throughout the body express the high-affinity neurotrophin receptor TrkA and the low-affinity receptor p75NTR. NGF is essential for glucose-stimulated insulin secretion and the complete development of pancreatic islets. Plus, this factor is involved in regulating lipolysis and thermogenesis in adipose tissue. Immune cells produce and respond to NGF, modulating their inflammatory phenotype and the secretion of cytokines, contributing to insulin resistance and metabolic homeostasis. This neurotrophin regulates the synthesis of gonadal steroid hormones, which ultimately participate in the metabolic homeostasis of other tissues. Therefore, we propose that this neurotrophin's imbalance in concentrations and signaling during metabolic syndrome contribute to its pathophysiology. In the present work, we describe the multiple roles of NGF in immunoendocrine organs that are important in metabolic homeostasis and related to the pathophysiology of metabolic syndrome.