Whole-body Homeostasis Research Articles

Neuroimmune mechanisms and therapies mediating post-ischaemic brain injury and repair

The nervous and immune systems control whole-body homeostasis and respond to various types of tissue injury, including stroke, in a coordinated manner. Cerebral ischaemia and subsequent neuronal cell death activate resident or infiltrating immune cells, which trigger neuroinflammation that affects functional prognosis after stroke. Inflammatory immune cells exacerbate ischaemic neuronal injury after the onset of brain ischaemia; however, some of the immune cells thereafter change their function to neural repair. The recovery processes after ischaemic brain injury require additional and close interactions between the nervous and immune systems through various mechanisms. Thus, the brain controls its own inflammation and repair processes after injury via the immune system, which provides a promising therapeutic opportunity for stroke recovery.

Nitrogen transporters along the intestinal spiral valve of cloudy catshark (Scyliorhinus torazame): Rhp2, Rhbg, UT

As part of their osmoregulatory strategy, marine elasmobranchs retain large quantities of urea to balance the osmotic pressure of the marine environment. The main source of nitrogen used to synthesize urea comes from the digestion and absorption of food across the gastrointestinal tract. In this study we investigated possible mechanisms of nitrogen movement across the spiral valve of the cloudy catshark (Scyliorhinus torazame) through the molecular identification of two Rhesus glycoprotein ammonia transporters (Rhp2 and Rhbg) and a urea transporter (UT). We used immunohistochemistry to determine the cellular localizations of Rhp2 and UT. Within the spiral valve, Rhp2 was expressed along the apical brush border membrane, and UT was expressed along the basolateral membrane and the blood vessels. The mRNA abundance of Rhp2 was significantly higher in all regions of the spiral valve of fasted catsharks compared to fed catsharks. The mRNA abundance of UT was significantly higher in the anterior spiral valve of fasted catsharks compared to fed. The mRNA transcript of four ornithine urea cycle (OUC) enzymes were detected along the length of the spiral valve and in the renal tissue, indicating the synthesis of urea via the OUC occurs in these tissues. The presence of Rhp2, Rhbg, and UT along the length of the spiral valve highlights the importance of ammonia and urea movement across the intestinal tissues, and increases our understanding of the mechanisms involved in maintaining whole-body nitrogen homeostasis in the cloudy catshark.

Three-dimensional visualization of neural networks inside bone by Osteo-DISCO protocol and alteration of bone remodeling by surgical nerve ablation

Bone is one of the largest organ systems in humans and is considered to regulate whole-body homeostasis in cooperation with other organs. We have previously reported that a sympathetic or sensory nervous system inside bone regulates bone homeostasis. However, the detailed regulatory mechanism, including the distribution of nerves inside bone, remains unknown. Although a two-dimensional histological analysis has been widely used to evaluate the structure of nerves or blood vessels, the actual structure is more complex, suggesting that it should be evaluated three-dimensionally. Here, we established a novel bone tissue clearing technique (Osteo-DISCO) for murine bones which enabled us to visualize the detailed distribution of nerves or blood vessels inside bone. Interestingly, we found that there is a specific nerve entry site in each long bone and that surgical ablation of the specific nerve fibers entering bone tissue led to decreased bone formation and impaired bone regeneration. Furthermore, we revealed that the administration of calcitonin gene-related peptide (CGRP), which is primarily released from sensory nerves, suppressed the bone loss caused by surgical nerve ablation. An in vitro study also indicated that CGRP directly promotes osteoblast activity, suggesting that sensory nerves inside bone can regulate osteogenesis via the secretion of CGRP.

Network-level analysis of ageing and its relationship with diseases and tissue regeneration in the mouse liver

The liver plays a vital role in maintaining whole-body metabolic homeostasis, compound detoxification and has the unique ability to regenerate itself post-injury. Ageing leads to functional impairment of the liver and predisposes the liver to non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Mapping the molecular changes of the liver with ageing may help to understand the crosstalk of ageing with different liver diseases. A systems-level analysis of the ageing-induced liver changes and its crosstalk with liver-associated conditions is lacking. In the present study, we performed network-level analyses of the ageing liver using mouse transcriptomic data and a protein–protein interaction (PPI) network. A sample-wise analysis using network entropy measure was performed, which showed an increasing trend with ageing and helped to identify ageing genes based on local entropy changes. To gain further insights, we also integrated the differentially expressed genes (DEGs) between young and different age groups with the PPI network and identified core modules and nodes associated with ageing. Finally, we computed the network proximity of the ageing network with different networks of liver diseases and regeneration to quantify the effect of ageing. Our analysis revealed the complex interplay of immune, cancer signalling, and metabolic genes in the ageing liver. We found significant network proximities between ageing and NAFLD, HCC, liver damage conditions, and the early phase of liver regeneration with common nodes including NLRP12, TRP53, GSK3B, CTNNB1, MAT1 and FASN. Overall, our study maps the network-level changes of ageing and their interconnections with the physiology and pathology of the liver.

Role of hepatic deiodinases in thyroid hormone homeostasis and liver metabolism, inflammation, and fibrosis.

Thyroid hormones play an essential role in regulating whole-body homeostasis. Deiodinases are known to convert thyroid hormone from the prohormone thyroxine (T4) to the bioactive hormone tri-iodothyronine (T3) and convert both T4 and T3 toward their inactive metabolites 3,3',5'-tri-iodothyronine (rT3) and 3,3'-di-iodothyronine (3,3'-T2). Deiodinases are thus important for the regulation of intracellular thyroid hormone concentrations. This is known to be crucial both during development and adult life in regulating thyroid hormone-related gene transcription. This review discusses the importance of liver deiodinases in determining serum and liver thyroid hormone concentrations, liver metabolism and liver disease.

Inguinal Fat Compensates Whole Body Metabolic Functionality in Partially Lipodystrophic Mice with Reduced PPARγ Expression.

Peroxisome proliferator-activated receptor γ (PPARγ) gene mutations in humans and mice lead to whole-body insulin resistance and partial lipodystrophy. It is unclear whether preserved fat depots in partial lipodystrophy are beneficial for whole-body metabolic homeostasis. We analyzed the insulin response and expression of metabolic genes in the preserved fat depots of PpargC/- mice, a familial partial lipodystrophy type 3 (FPLD3) mouse model resulting from a 75% decrease in Pparg transcripts. Perigonadal fat of PpargC/- mice in the basal state showed dramatic decreases in adipose tissue mass and insulin sensitivity, whereas inguinal fat showed compensatory increases. Preservation of inguinal fat metabolic ability and flexibility was reflected by the normal expression of metabolic genes in the basal or fasting/refeeding states. The high nutrient load further increased insulin sensitivity in inguinal fat, but the expression of metabolic genes became dysregulated. Inguinal fat removal resulted in further impairment of whole-body insulin sensitivity in PpargC/- mice. Conversely, the compensatory increase in insulin sensitivity of the inguinal fat in PpargC/- mice diminished as activation of PPARγ by its agonists restored insulin sensitivity and metabolic ability of perigonadal fat. Together, we demonstrated that inguinal fat of PpargC/- mice plays a compensatory role in combating perigonadal fat abnormalities.

Effects of Vitamin D on Cardiovascular Risk and Oxidative Stress.

Vitamin D has been primarily studied as an important factor influencing bone and calcium metabolism. Metabolites of vitamin D are essential for whole-body calcium homeostasis, maintaining serum calcium levels within a narrow range by regulating this process in the bones and gut. Nevertheless, its deficiency is also related to increased risk of type 2 diabetes mellitus (T2DM), metabolic syndrome (MS), and cardiovascular disease (CVD)-with increased visceral adipose tissue and body mass index (BMI), as well as the frequently associated hypercholesterolemia. It has been reported that vitamin D levels are inversely related to cardiovascular (CV) risk in men and women. However, the effects of vitamin D on distinct outcomes in women and the dose of supplementation needed to improve clinical endpoints have not been established. 25-Hydroxyvitamin D [25(OH)D] reduces systemic inflammatory mediators in CVD and favors the release of anti-inflammatory cytokines from the immune system. In addition, 25(OH)D can be primarily converted into calcitriol (1,25-dihydroxycholecalciferol [1,25(OH)2D]) in the kidneys through the action of the 1-α-hydroxylase enzyme. Calcitriol, through the downregulation mechanism of renin expression, renin-angiotensin-aldosterone system (RAAS) activity, and its interaction with the vitamin D receptor, can bring CV benefits. The calcitriol form also lowers parathyroid hormone (PTH) levels by indirectly causing a reduction in aldosterone and mineralocorticoid synthesis. Elevated plasma aldosterone is related to endothelial dysfunction and CVD in hypovitaminosis D status. Vitamin D supplementation may benefit certain risk groups, as it improves metabolic variables, reducing oxidative stress and CV outcomes. More studies are needed to define interventions with vitamin D in men and women.

Adipocyte Thyroid Hormone β Receptor-Mediated Hormone Action Fine-tunes Intracellular Glucose and Lipid Metabolism and Systemic Homeostasis.

How thyroid hormone (TH) achieves its diverse biological activities in the regulation of metabolism is not fully understood. Whether TH regulates systemic metabolic homeostasis via its action on white adipose tissue is unclear. Adipocyte TH receptor (TR) β mediates the triiodothyronine effect on multiple metabolic pathways by targeting glucose-responsive lipogenic transcription factor in white adipose tissue; mice lacking adipocyte TRβ are susceptible to high-fat diet-induced metabolic abnormalities. TRβ in white adipocytes controls intracellular and systemic metabolism and may be a potential target for metabolic diseases.

Pancreatic Hormone Insulin Modulates Organic Anion Transporter 1 in the Kidney: Regulation via Remote Sensing and Signaling Network.

Organic anion transporter 1 (OAT1) expressed in the kidney plays an important role in the elimination of numerous anionic drugs used in the clinic. We report here that insulin, a pancreas-secreted hormone, regulated the expression and activity of kidney-specific OAT1 both in cultured cells and in rats. We showed that treatment of OAT1-expressing cells with insulin led to an increase in OAT1 expression, transport activity, and SUMOylation. Such insulin-induced increase was blocked by afuresertib, a specific inhibitor for protein kinase B (PKB), suggesting insulin regulates OAT1 through PKB signaling pathway. Furthermore, insulin stimulated transport activity and SUMOylation of endogenously expressed OAT1 in rat kidneys. In conclusion, our data support a remote sensing and signaling model, in which OAT1 plays an essential role in intercellular and inter-organ communication and in maintaining local and whole-body homeostasis. Such complex and dedicated communication is carried out by insulin, and PKB signaling and membrane sorting.

Gut Microbial-Derived Short Chain Fatty Acids: Impact on Adipose Tissue Physiology.

Obesity is a global public health issue and major risk factor for pathological conditions, including type 2 diabetes, dyslipidemia, coronary artery disease, hepatic steatosis, and certain types of cancer. These metabolic complications result from a combination of genetics and environmental influences, thus contributing to impact whole-body homeostasis. Mechanistic animal and human studies have indicated that an altered gut microbiota can mediate the development of obesity, leading to inflammation beyond the intestine. Moreover, prior research suggests an interaction between gut microbiota and peripheral organs such as adipose tissue via different signaling pathways; yet, to what degree and in exactly what ways this inter-organ crosstalk modulates obesity remains elusive. This review emphasizes the influence of circulating gut-derived short chain fatty acids (SCFAs) i.e., acetate, propionate, and butyrate, on adipose tissue metabolism in the scope of obesity, with an emphasis on adipocyte physiology in vitro and in vivo. Furthermore, we discuss some of the well-established mechanisms via which microbial SCFAs exert a role as a prominent host energy source, hence regulating overall energy balance and health. Collectively, exploring the mechanisms via which SCFAs impact adipose tissue metabolism appears to be a promising avenue to improve metabolic conditions related to obesity.

Dietary Thymoquinone Alone or Combined with Swimming Exercise Protect against Microcystin-LR-Induced Oxidative Injury in Mice.

Microcystin-leucine-arginine (MCLR) is the most abundant cyanotoxin produced by cyanobacteria. It induces potent cytotoxicity through oxidative stress and DNA damage. Thymoquinone (TQ) is a natural nutraceutical antioxidant derived from black cumin (Nigella sativa). Physical exercise (EX) improves whole-body metabolic homeostasis. Therefore, this study examined the protective role of swimming exercise and TQ against MC-induced toxicity in mice. Fifty-six healthy adult male albino mice (25-30 g) were randomized into seven groups; group (I) was the negative control and received oral physiological saline for 21 days; group (II) received water EX for 30 min daily; group (III) was intraperitoneally injected with TQ (5 mg/kg daily, for 21 days); group (IV) was intraperitoneally administered MC (10 μg/kg daily, for 14 days) and acted as the positive toxic control; group (V) was treated with MC and water EX; group (VI) was injected with MC and TQ; finally, group (VII) was treated with MC with TQ and water EX. In comparison with the control group, the results showed hepatic, renal, and cardiac toxicity in the MCLR-treated group, indicated by a significant increase (p < 0.05) in serum levels of alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transferase (ALT), cholesterol, lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase-myocardial band (CK-MB), urea, creatinine, interleukin-6, interleukin -1β, and tumor necrosis factor-α levels. In addition, there were significant elevations (p < 0.05) in malondialdehyde (MDA) and nitric oxide (NO) levels and a significant decrease in reduced glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) in hepatic, cardiac, and renal tissues. Treatment with either TQ or water EX significantly improved (p < 0.05) the MC-induced toxicity with superiority of the TQ group in the restoration of normal ranges; however, cotreatment with both TQ and swimming EX showed the most improvement and restoration to normal ranges as a result of increasing EX clinical efficacy by TQ.

Effect of Fennel (Foeniculum Vulgare) Seed Powder Consumption on Insulin-like Growth Factor 1 Gene Expression in the Liver Tissue of Growing Lambs

Background and objectivesToday, medicinal plants and phytobiotics that contain flavonoids, alkaloids, and essential oils are widely used in animal feed. These additives have many benefits, including increasing liver function and preventing certain diseases. The liver is one of the organs that plays a key role in insulin-mediated regulation of metabolism as well as in glucose, whole-body, and lipid homeostasis. The aim of this study was to investigate the effect of fennel (Foeniculum vulgare) seed powder consumption on insulin-like growth factor 1 (IGF1) gene expression in the liver tissue of growing lambs.

Seawater fish use an electrogenic boric acid transporter, Slc4a11A, for boric acid excretion by the kidney

Boric acid is a vital micronutrient in animals; however, excess amounts are toxic to them. Little is known about whole-body boric acid homeostasis in animals. Seawater (SW) contains 0.4mM boric acid, and since marine fish drink SW, their urinary system was used here as a model of the boric acid excretion system. We determined that the bladder urine of a euryhaline pufferfish (river pufferfish, Takifugu obscurus) acclimated to fresh water and SW contained 0.020 and 19mM of boric acid, respectively (a 950-fold difference), indicating the presence of a powerful excretory renal system for boric acid. Slc4a11 is a potential animal homolog of the plant boron transporter BOR1; however, mammalian Slc4a11 mediates H+ (OH-) conductance but does not transport boric acid. We found that renal expression of the pufferfish paralog of Slc4a11, Slc4a11A, was markedly induced after transfer from fresh water to SW, and Slc4a11A was localized to the apical membrane of kidney tubules. When pufferfish Slc4a11A was expressed in Xenopus oocytes, exposure to media containing boric acid and a voltage clamp elicited whole-cell outward currents, a marked increase in pHi, and increased boron content. In addition, the activity of Slc4a11A was independent of extracellular Na+. These results indicate that pufferfish Slc4a11A is an electrogenic boric acid transporter that functions as a B(OH)4- uniporter, B(OH)3-OH- cotransporter, or B(OH)3/H+ exchanger. These observations suggest that Slc4a11A is involved in the kidney tubular secretion of boric acid in SW fish, probably induced by the negative membrane potential and low pH of urine.

Linc-RAM is a metabolic regulator maintaining whole-body energy homeostasis in mice.

Long noncoding RNAs (lncRNAs) are known to have profound functions in regulating cell fate specification, cell differentiation, organogenesis, and disease, but their physiological roles in controlling cellular metabolism and whole-body metabolic homeostasis are less well understood. We previously identified a skeletal muscle-specific long intergenic noncoding RNA (linc-RNA) activator of myogenesis, Linc-RAM, which enhances muscle cell differentiation during development and regeneration. Here, we report that Linc-RAM exerts a physiological function in regulating skeletal muscle metabolism and the basal metabolic rate to maintain whole-body metabolic homeostasis. We first demonstrate that Linc-RAM is preferentially expressed in type-II enriched glycolytic myofibers, in which its level is more than 60-fold higher compared to that in differentiated myotubes. Consistently, genetic deletion of the Linc-RAM gene in mice increases the expression levels of genes encoding oxidative fiber versions of myosin heavy chains and decreases those of genes encoding rate-limiting enzymes for glycolytic metabolism. Physiologically, Linc-RAM-knockout mice exhibit a higher basal metabolic rate, elevated insulin sensitivity and reduced fat deposition compared to their wild-type littermates. Together, our findings indicate that Linc-RAM is a metabolic regulator of skeletal muscle metabolism and may represent a potential pharmaceutical target for preventing and/or treating metabolic diseases, including obesity.

OR23-4 Intestinal FFA2 and FFA3 Mediate Obesogenic Effects in Mice on a Western Diet

Abstract Free fatty acid receptor 2 and free fatty acid receptor 3 (FFA2/3) are two highly similar G protein-coupled receptors belonging to the free fatty acid receptor family. Their ligands are short-chain fatty acids (SCFAs), which are key nutrients that play a diverse role in physiological function, including the regulation of metabolic homeostasis and glycemic control. FFA2/3 are broadly expressed in a multitude of tissues including the intestine, pancreas, adipose and central nervous system, where they contribute to metabolic homeostasis via a summation of tissue-specific effects. Consequently, FFA2/3 have been identified as a potential drug target for metabolic diseases including obesity and type-2 diabetes. Both FFA2 and FFA3 are highly expressed within the intestinal epithelium – the major site of SCFA generation – and have been identified in hormone-secreting enteroendocrine cells as well as intestinal epithelial cells. However, due conflicting data, the respective roles of FFA2/3 within the intestine and their effects on physiology and metabolism are still largely unclear. Previous in vivo studies involving this receptor have largely relied on global knockout mouse models, making it difficult to isolate their effects in the intestine. To overcome this challenge, we generated a novel intestine-specific knockout mouse model for FFA2 and FFA3 individually, utilizing Cre-mediated recombination under the expression of the villin promoter. Here, we report the first in vivo characterization of FFA2/3 in the intestine and reveal novel insights into receptor function. Following model validation, we conducted a general metabolic assessment of male Villin-Cre-FFA2 (Vil-FFA2) and Villin-Cre-FFA3 (Vil-FFA3) mice on standard chow and observed no major congenital or time-dependent defects. Because dietary changes are known to alter gut microbial composition, and thereby SCFA production, a pilot study was performed on male Vil-FFA2 and Vil-FFA3 mice and their littermate controls to probe for a phenotype on a high-fat, high-sugar "western diet." Mice were placed on either a low-fat control diet (CD) or western diet (WD) at 10 weeks of age and metabolically profiled for 25 weeks. We found that both Vil-FFA2 and Vil-FFA3 mouse strains were largely protected from diet-induced obesity and had significantly lower fat mass as well as adipose hypertrophy. Additionally, both mouse strains had reduced intestinal inflammation and improved glucose homeostasis. These differences were driven by lower food intake in the Vil-FFA2 strain only. Our findings suggest a novel role of FFA2/3 in mediating the metabolic consequences of a western diet – a state of high inflammation, dysbiosis and metabolic stress. Moreover, these data support an intestine-specific role of FFA2/3 in whole-body metabolic homeostasis and in the development of adiposity and hyperglycemia. Presentation: Monday, June 13, 2022 12:00 p.m. - 12:15 p.m.

Exposure to environmental contaminants and folic acid supplementation intergenerationally impact fetal skeleton development through the paternal lineage in a rat model.

Persistent organic pollutants (POPs) are ubiquitous in the environment, which is of concern since they are broadly toxic for wildlife and human health. It is generally accepted that maternal prenatal folic acid supplementation (FA) may beneficially impact offspring development, but it has been recently shown that the father's exposures also influence the health of his offspring. Bone is an endocrine organ essential for whole-body homeostasis and is susceptible to toxicants. Herein, we tested the hypotheses that prenatal paternal exposure to POPs induces developmental bone disorders in fetuses across multiple generations and that FA supplementation attenuates these disorders. We used a four-generation rat model, in which F0 founder females were divided into four treatment groups. F0 females were gavaged with corn oil or an environmentally-relevant POPs mixture and fed either a control diet (2 mg FA/kg), or FA supplemented diet (6 mg FA/kg) before mating and until parturition (four treatments in total). After the birth of the F1 litters, all F0 females and subsequent generations received the FA control diet. Staining with alcian blue and alizarin red S of male and female fetal skeletons was performed at Gestational Day 19.5. Paternal direct and ancestral exposure to POPs delayed bone ossification and decreased the length of long limb bones in fetuses. Maternal FA supplementation did not counteract the POPs-associated delayed fetal ossification and reduced long bone length. In conclusion, prenatal paternal POPs exposure causes developmental bone abnormalities over multiple generations, which were not corrected by maternal FA supplementation.

Exon 2-mediated deletion of Trem2 does not worsen metabolic function in diet-induced obese mice.

Triggering receptor expressed on myeloid cells 2 (Trem2) is highly expressed on myeloid cells and is involved in cellular lipid homeostasis and inflammatory processes. Trem2 deletion in mice (Trem2-/- ) evokes adipose tissue dysfunction, but its role in worsening obesity-induced metabolic dysfunction has not been resolved. Here we aimed to determine the causal role of Trem2 in regulating glucose homeostasis and insulin sensitivity in mice. Nine-week-old male and female littermate wild-type (WT) and Trem2-/- mice were fed a low- or high-fat diet for 18weeks and phenotyped for metabolic function. Diet-induced weight gain was similar between genotypes, irrespective of sex. Consistent with previous reports, we find that loss of Trem2 causes massive adipocyte hypertrophy and an attenuation in the lipid-associated macrophage transcriptional response to obesity. In contrast to published data, we find that loss of Trem2 does not worsen metabolic function in obese mice. No differences in intraperitoneal glucose tolerance (ipGTT), oral GTT or mixed meal substrate control, including postprandial glucose, non-esterified fatty acids, insulin or triglycerides, were found between WT and Trem2-/- animals. Similarly, no phenotypic differences existed when animals were challenged with stressors on metabolic demand (i.e. acute exercise or environmental temperature modulation). Collectively, we report a disassociation between adipose tissue remodelling caused by loss of Trem2 and whole-body metabolic homeostasis in obese mice. The complementary nature of experiments conducted gives credence to the conclusion that loss of Trem2 is unlikely to worsen glucose homeostasis in mice.

Spatially resolved characterization of tissue metabolic compartments in fasted and high-fat diet livers.

Cells adapt their metabolism to physiological stimuli, and metabolic heterogeneity exists between cell types, within tissues, and subcellular compartments. The liver plays an essential role in maintaining whole-body metabolic homeostasis and is structurally defined by metabolic zones. These zones are well-understood on the transcriptomic level, but have not been comprehensively characterized on the metabolomic level. Mass spectrometry imaging (MSI) can be used to map hundreds of metabolites directly from a tissue section, offering an important advance to investigate metabolic heterogeneity in tissues compared to extraction-based metabolomics methods that analyze tissue metabolite profiles in bulk. We established a workflow for the preparation of tissue specimens for matrix-assisted laser desorption/ionization (MALDI) MSI that can be implemented to achieve broad coverage of central carbon, nucleotide, and lipid metabolism pathways. Herein, we used this approach to visualize the effect of nutrient stress and excess on liver metabolism. Our data revealed a highly organized metabolic tissue compartmentalization in livers, which becomes disrupted under high fat diet. Fasting caused changes in the abundance of several metabolites, including increased levels of fatty acids and TCA intermediates while fatty livers had higher levels of purine and pentose phosphate-related metabolites, which generate reducing equivalents to counteract oxidative stress. This spatially conserved approach allowed the visualization of liver metabolic compartmentalization at 30 μm pixel resolution and can be applied more broadly to yield new insights into metabolic heterogeneity in vivo.

MOTS-c promotes muscle differentiation in vitro

MOTS-c (mitochondrial open reading frame of the 12 S rRNA-c) is a newly discovered peptide that has been shown to have a protective role in whole-body metabolic homeostasis. This could be a consequence of the effect of MOTS-c on muscle tissue. Here, we investigated the role of MOTS-c in the differentiation of human (LHCN-M2) and murine (C2C12) muscle progenitor cells. Cells were treated with peptides at the onset of differentiation or after myotubes had been formed. We identified in silico a putative Src Homology 2 (SH2) binding motif in the YIFY region of the MOTS-c sequence, and created a Y8F mutant MOTS-c peptide to explore the role of this region. In both cellular models, treatment with wild-type MOTS-c peptide increased myotube formation whereas treatment with the Y8F peptide did not. MOTS-c wild-type, but not Y8F peptide, also protected against interleukin-6 (IL-6)-induced reduction of nuclear myogenin staining in myocytes. Thus, we investigated whether MOTS-c interacts with the IL-6/Janus kinase/ Signal transducer and activator of transcription 3 (STAT3) pathway, and found that MOTS-c, but not the Y8F peptide, blocked the transcriptional activity of STAT3 induced by IL-6. Altogether, our findings suggest that, in muscle cells, MOTS-c interacts with STAT3 via the putative SH2 binding motif in the YIFY region to reduce STAT3 transcriptional activity, which enhances myotube formation. This newly discovered mechanism of action highlights MOTS-c as a potential therapeutic target against muscle-wasting in several diseases.

Cross-Talk Between Gut Microbiota and Adipose Tissues in Obesity and Related Metabolic Diseases.

The rapid increase of obesity and associated diseases has become a major global health problem. Adipose tissues are critical for whole-body homeostasis. The gut microbiota has been recognized as a significant environmental factor in the maintenance of energy homeostasis and host immunity. A growing body of evidence suggests that the gut microbiota regulates host metabolism through a close cross-talk with adipose tissues. It modulates energy expenditure and alleviates obesity by promoting energy expenditure, but it also produces specific metabolites and structural components that may act as the central factors in the pathogenesis of inflammation, insulin resistance, and obesity. Understanding the relationship between gut microbiota and adipose tissues may provide potential intervention strategies to treat obesity and associated diseases. In this review, we focus on recent advances in the gut microbiota and its actions on adipose tissues and highlight the joint actions of the gut microbiota and adipose tissue with each other in the regulation of energy metabolism.