Regulation Of Systemic Metabolism Research Articles

Deletion of the Alzheimer's disease risk gene Abi3 locus results in obesity and systemic metabolic disruption in mice.

Alzheimer's disease (AD) genetics studies have identified a coding variant within ABI3 gene that increases the risk of developing AD. Recently, we demonstrated that deletion of the Abi3 gene locus dramatically exacerbates AD neuropathology in a transgenic mouse model of amyloidosis. In the course of this AD project, we unexpectedly found that deletion of the Abi3 gene locus resulted in a dramatic obese phenotype in non-transgenic mice. Here, we report our investigation into this serendipitous metabolic finding. Specifically, we demonstrate that mice with deletion of the Abi3 gene locus (Abi3-/- ) have dramatically increased body weight and body fat. Further, we determined that Abi3-/- mice have impaired energy expenditure. Additionally, we found that deletion of the Abi3 gene locus altered gene expression within the hypothalamus, particularly within immune-related pathways. Subsequent immunohistological analysis of the central nervous system (CNS) revealed that microglia number and area were decreased specifically within the mediobasal hypothalamus of Abi3-/- mice. Altogether, this investigation establishes the functional importance of the Abi3 gene locus in the regulation of systemic metabolism and maintenance of healthy body weight. While our previous findings indicated the importance of Abi3 in neurodegeneration, this study indicates that Abi3 related functions are also essential for metabolic regulation.

Diagnostic, Prognostic, and Immunological Roles of FABP4 in Pancancer: A Bioinformatics Analysis.

Fatty acid binding protein 4 (FABP4) is mainly involved in the regulation of systemic metabolism through various lipid signaling pathways. Metabolic reprogramming is one of the important factors in the development and progression of cancer. It has been recently reported that FABP4 is closely related to the development of cancer and may be involved in tumor invasion and metastasis. In this study, we explored the expression pattern of FABP4 in pancancer through TCGA and CPTAC. Using TCGA, Kaplan-Meier Plotter, and STRING databases, to explore its diagnostic and prognostic value, and function through GO/KEGG and GSEA. Then, using the TIMER2.0 database, we investigated the correlation between FABP4 expression and immune infiltration in cancers, especially stomach adenocarcinomas (STAD) and colorectal adenocarcinoma (COADREAD). Compared with normal tissues, the expression of FABP4 in more than 10 tumor tissues was lower (p < 0.05). Through the receiver operating characteristic (ROC) curve, the diagnostic value was found higher in colorectal cancer, breast cancer, thyroid cancer, and lung cancer, with the area under the curve (AUC) > 0.9. Through the K-M curve, FABP4 was found to correlate to the prognosis of various cancers. The results of gastric cancer and colorectal cancer are consistent. The low-expression group has a better prognosis than the high-expression group, and the expression of FABP4 in the early T and N stages of gastrointestinal tumors is lower. FABP4 highly expressed gene set is mostly enriched in extracellular matrix degradation and cell adhesion functions. Gastrointestinal tumors with high expression of FABP4 may have more immunosuppressive effects on macrophages and have a worse prognosis. FABP4 can be used as a diagnostic and prognostic biomarker in pancancer, and its high expression in gastrointestinal tumors suggests poor prognosis. This may be correlated to the immune infiltration of macrophages and epithelial-mesenchymal transition.

&lt;i&gt;Komagataella phaffii&lt;/i&gt; yeast as a model organism in biotechnology and fundamental research

The choice of a model organism in biology is based on various factors, such as practical significance and ease of manipulation. Saccharomyces cerevisiae yeast is one of the most widely used and well-studied eukaryotic models. However, developments in NGS, proteomics, metabolomics and gene editing methods allow other species to become the object of fundamental research. A good example of such emerging model organisms is the yeast Komagataella phaffii.&#x0D; K. phaffii belongs to a unique group of eukaryotic methylotrophs that can use methanol as the sole source of carbon and energy. On the other hand, K. phaffii seems to be more characteristic of the common ancient yeast ancestors than the rapidly evolving S. cerevisiae. Comparative studies between S. cerevisiae and K. phaffii will shed light on the mechanisms of evolution of metabolic pathways and regulatory systems. Such studies are accelerated by the practical importance of K. phaffii as a common microbial production host in biotechnology.&#x0D; In our studies, we demonstrate that some amino acids greatly affect gene expression in K. phaffii [1]. Transcriptome analysis revealed drastic changes in gene expression when proline was present in the media. About 18.9% of total protein-coding genes were differentially expressed, including genes involved in methanol utilization [2]. Our results show that the unique methanol metabolism pathway is regulated not only by methanol, but also by other carbon sources. Therefore, our findings suggest that the regulation of methanol metabolism pathway is integrated into other cellular regulatory networks. Methanol metabolism, acquired by K. phaffii during evolution, is tightly associated with nitrogen an amino acid metabolism.

Role of bile acids in overweight and obese children and adolescents.

Bile acids (BAs) are amphipathic molecules synthetized in the liver. They are primarily involved in the digestion of nutrients. Apart from their role in dietary lipid absorption, BAs have progressively emerged as key regulators of systemic metabolism and inflammation. In the last decade, it became evident that BAs are particularly important for the regulation of glucose, lipid, and energy metabolism. Indeed, the interest in role of BA in metabolism homeostasis is further increased due to the global public health increase in obesity and related complications and a large number of research postulating that there is a close mutual relationship between BA and metabolic disorders. This strong relationship seems to derive from the role of BAs as signaling molecules involved in the regulation of a wide spectrum of metabolic pathways. These actions are mediated by different receptors, particularly nuclear farnesoid X receptor (FXR) and Takeda G protein coupled receptor 5 (TGR5), which are probably the major effectors of BA actions. These receptors activate transcriptional networks and signaling cascades controlling the expression and activity of genes involved in BA, lipid and carbohydrate metabolism, energy expenditure, and inflammation. The large correlation between BAs and metabolic disorders offers the possibility that modulation of BAs could be used as a therapeutic approach for the treatment of metabolic diseases, including obesity itself. The aim of this review is to describe the main physiological and metabolic actions of BA, focusing on its signaling pathways, which are important in the regulation of metabolism and might provide new BA -based treatments for metabolic diseases.

Endocrinal metabolic regulation on the skeletal system in post-menopausal women.

Osteoporosis is a common endocrinologic disorder characterized as a chronic bone loss condition. Sexual dimorphism is ubiquitous in the incidence of osteoporosis with post-menopausal women being acutely affected. Gonadal sex hormones including estrogen act as crucial regulators of bone mass; therefore, loss of such hormones leads to an imbalance in skeletal turnover leading to osteoporosis. Estrogen can influence both bone formation as well as resorption by reducing osteoblast activity and enhancing osteoclastogenesis. Additionally, estrogen is a potent regulator of systemic metabolism. Recent studies have provided clues that estrogenic effect on bone might also involve alterations in bone cell metabolism and bioenergetic potential. While direct effects of gonadal hormones ability to alter intracellular metabolism of bone cells has not been studied, there is precedence within the literature that this is occurring and contributing to post-menopausal bone loss. This review aims to serve as a perspective piece detailing the prospective role of gonadal hormones regulating bone cell metabolic potential.

A potent physiological method to magnify and sustain soleus oxidative metabolism improves glucose and lipid regulation

SummarySlow oxidative muscle, most notably the soleus, is inherently well equipped with the molecular machinery for regulating blood-borne substrates. However, the entire human musculature accounts for only ∼15% of the body’s oxidative metabolism of glucose at the resting energy expenditure, despite being the body’s largest lean tissue mass. We found the human soleus muscle could raise local oxidative metabolism to high levels for hours without fatigue, during a type of soleus-dominant activity while sitting, even in unfit volunteers. Muscle biopsies revealed there was minimal glycogen use. Magnifying the otherwise negligible local energy expenditure with isolated contractions improved systemic VLDL-triglyceride and glucose homeostasis by a large magnitude, e.g., 52% less postprandial glucose excursion (∼50 mg/dL less between ∼1 and 2 h) with 60% less hyperinsulinemia. Targeting a small oxidative muscle mass (∼1% body mass) with local contractile activity is a potent method for improving systemic metabolic regulation while prolonging the benefits of oxidative metabolism.

Probiotics and Gut Microbiota in Obesity: Myths and Realities of a New Health Revolution.

Obesity and its comorbidities are humans’ most prevalent cardio-metabolic diseases worldwide. Recent evidence has shown that chronic low-grade inflammation is a common feature in all highly prevalent chronic degenerative diseases. In this sense, the gut microbiota is a complete ecosystem involved in different processes like vitamin synthesis, metabolism regulation, and both appetite and immune system control. Thus, dysbiosis has been recognised as one of the many factors associated with obesity due to a predominance of Firmicutes, a decrease in Bifidobacterium in the gut, and a consequent short-chain fatty acids (SCFA) synthesis reduction leading to a reduction in incretins action and intestinal permeability increase. In this context, bacteria, bacterial endotoxins, and toxic bacterial by-products are translocated to the bloodstream, leading to systemic inflammation. This review focuses on gut microbiota composition and its role in obesity, as well as probiotics and prebiotics benefits in obesity.

Metabolic Impact of MKP-2 Upregulation in Obesity Promotes Insulin Resistance and Fatty Liver Disease.

The mechanisms connecting obesity with type 2 diabetes, insulin resistance, nonalcoholic fatty liver disease, and cardiovascular diseases remain incompletely understood. The function of MAPK phosphatase-2 (MKP-2), a type 1 dual-specific phosphatase (DUSP) in whole-body metabolism, and how this contributes to the development of diet-induced obesity, type 2 diabetes (T2D), and insulin resistance is largely unknown. We investigated the physiological contribution of MKP-2 in whole-body metabolism and whether MKP-2 is altered in obesity and human fatty liver disease using MKP-2 knockout mice models and human liver tissue derived from fatty liver disease patients. We demonstrate that, for the first time, MKP-2 expression was upregulated in liver tissue in humans with obesity and fatty liver disease and in insulin-responsive tissues in mice with obesity. MKP-2-deficient mice have enhanced p38 MAPK, JNK, and ERK activities in insulin-responsive tissues compared with wild-type mice. MKP-2 deficiency in mice protects against diet-induced obesity and hepatic steatosis and was accompanied by improved glucose homeostasis and insulin sensitivity. Mkp-2−/− mice are resistant to diet-induced obesity owing to reduced food intake and associated lower respiratory exchange ratio. This was associated with enhanced circulating insulin-like growth factor-1 (IGF-1) and stromal cell-derived factor 1 (SDF-1) levels in Mkp-2−/− mice. PTEN, a negative regulator of Akt, was downregulated in livers of Mkp-2−/− mice, resulting in enhanced Akt activity consistent with increased insulin sensitivity. These studies identify a novel role for MKP-2 in the regulation of systemic metabolism and pathophysiology of obesity-induced insulin resistance and fatty liver disease.

1409-P: Revealing Heterogeneity in Human White Adipose Tissue at Single-Cell Level

White adipose tissue is characterized by substantial functional heterogeneity based on anatomic location and developmental lineages. Such differences may contribute to depot-dependent differences in adipose regulation of systemic metabolism and the relative impact of adipose distribution (e.g. subcutaneous, SQ, vs. intraabdominal, IA) on risk for type 2 diabetes. While mouse adipose depot heterogeneity at the single-cell level has recently been explored, comparative analysis of human white fat depots is still in its infancy.Hereby, we establish a single-nucleus RNA sequencing (snRNA Seq) method for isolating and sequencing intact single nuclei from frozen human WAT biopsies. Using this approach, we analyzed the transcriptome of individual nuclei from 22 WAT SQ or IA biopsies (SQ, 12 IA, 3 paired) acquired from subjects (16 females, 3 males) with or without type 2 diabetes (T2D) across a wide BMI range (Mean+/-SD = 45.4+/-10.3 kg/m2. Range: 23.6 - 60.9 kg/m2) . We show that both SQ and IA human fat depots demonstrate substantial cell-to-cell heterogeneity, and identify multiple adipose and non-adipose-related cell types resident in both tissues. Our analysis identifies several novel subclusters, including two distinct mature adipocyte subclusters, characterized by low vs. high adiponectin expression and thus potentially contributing to adipose-mediated effects on systemic metabolism. Moreover, we identify a novel cluster present in both SQ and IA depots, with a unique transcriptomic signature marked by DAPK1 and enrichment for hedgehog signaling and endocytosis KEGG terms. Comprehensive cross-sample integrative bioinformatics analysis using the software tools scVI and VISION reveals distinct molecular markers and transcriptomic signatures between depots, between clusters, and across a range of BMI, that may serve as promising targets for understanding the mechanism by which specific adipose-resident cell populations mediate metabolic risk associated with adiposity. Disclosure V.Efthymiou: None. S.Kodani: None. A.Gupta: None. F.Shamsi: None. A.Streets: None. Y.Tseng: Consultant; Cellarity. M.Patti: Consultant; AstraZeneca, Eiger BioPharmaceuticals, Hanmi Pharm. Co., Ltd., MBX Biosciences, Poxel SA, Other Relationship; Fractyl Health, Inc., Xeris Pharmaceuticals, Inc., Research Support; Dexcom, Inc. Funding Chan Zuckerberg Initiative (CZI)

The Multi-Omics Analysis Revealed a Metabolic Regulatory System of Cecum in Rabbit with Diarrhea.

Simple SummaryIn July 2020, China completely banned the addition of antibiotics to feed, which had a huge impact on animal husbandry, such as the increased incidence of some intestinal diseases. In this study, the pathogenesis of diarrhea in rabbits fed with antibiotic-free diet was studied by multi-omics analysis. The study found that the relative abundances of Firmicutes and Proteobacteria in the cecum of diarrhea-afflicted rabbits changed significantly. Most of the differential expression genes identified were related to cecum inflammation and immune response, and a total of 652 differential metabolites were identified, mainly involved in inflammation-related metabolic pathways such as bile secretion, folic acid resistance, and tryptophan metabolism. In addition, Fournierella was positively correlated with myricetin and ursolic acid; thus, it might further cause bile secretion and tryptophan metabolism disorders, aggravate intestinal inflammation, change intestinal permeability, reduce host immunity, and lead to diarrhea in rabbits.With the comprehensive prohibition of antibiotics in the feed industry in China, the incidence of diarrhea in rabbits increased, such as loss of appetite, vomiting, and excretion of atheromatous feces. In order to explore the pathological and the molecular mechanisms of the diarrhea in the rabbitry fed with antibiotic-free diet, we used microbial metagenomics, transcriptome, and non-targeted metabolomics sequencing. The results showed that the Firmicutes level was significantly decreased (p < 0.001) and the Proteobacteria level was significantly increased (p < 0.05). The functional enrichment of cecum revealed that most differentially expressed genes (DEGs) were expressed in immune, inflammatory, and metabolic processes. The enrichment of the cecal fecal metabolites focused on the bile secretion, antifolate resistance, and tryptophan metabolism pathways, which are mainly associated with inflammation. The results of correlation analysis showed that Fournierella was positively correlated with myricetin, ursolic acid, and furtherly might cause bile secretion and tryptophan metabolism disorder, aggravate intestinal inflammation, change intestinal permeability, and reduce host immunity, leading to diarrhea in rabbits. This study provides a theoretical basis for illustrating the reason for diarrhea and developing new feeds for the health of rabbits.

Effects of U on the growth, reactive oxygen metabolism and osmotic regulation in radish (Raphanus sativus L.).

Uranium (U) is a non-essential and toxic element, so it is necessary to study the physiological mechanism of plant response to U stress. The present study evaluated the growth status, reactive oxygen metabolism and osmotic regulation system in radish (Raphanus sativus) under U stress (0, 25, 50 and 100μM). The results showed that U had no significant effect on the germination of radish seeds but inhibited the growth of seedlings, such as reduced root activity and increased plasma membrane permeability. U is mainly distributed in radish roots, so it poisons the roots more than the aboveground parts. When U concentration was 25μM, superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) activities in radish were increased to cope with the oxidative stress caused by U stress, and the accumulation of proline and soluble sugar was increased to maintain cell turgor. However, under high concentration (100μM), the damage of radish root was serious; thus, the SOD, CAT and soluble sugar could not respond to U stress. In conclusion, the identification and characterization of U-stress responses in genuine U-tolerant plants would improve our knowledge on the detoxification of this radionuclide.

Serum Metabolomics Reveals Dysregulation and Diagnostic Potential of Oxylipins in Tumor-induced Osteomalacia.

Excessive production of fibroblast growth factor 23 (FGF23) by a tumor is considered the main pathogenesis in tumor-induced osteomalacia (TIO). Despite its importance to comprehensive understanding of pathogenesis and diagnosis, the regulation of systemic metabolism in TIO remains unclear. We aimed to systematically characterize the metabolome alteration associated with TIO. By means of liquid chromatography-tandem mass spectrometry-based metabolomics, we analyzed the metabolic profile from 96 serum samples (32 from TIO patients at initial diagnosis, pairwise samples after tumor resection, and 32 matched healthy control (HC) subjects). In order to screen and evaluate potential biomarkers, statistical analyses, pathway enrichment and receiver operating characteristic (ROC) were performed. Metabolomic profiling revealed distinct alterations between TIO and HC cohorts. Differential metabolites were screened and conducted to functional clustering and annotation. A significantly enriched pathway was found involving arachidonic acid metabolism. A combination of 5 oxylipins, 4-HDoHE, leukotriene B4, 5-HETE, 17-HETE, and 9,10,13-TriHOME, demonstrated a high sensitivity and specificity panel for TIO prediction screened by random forest algorithm (AUC = 0.951; 95% CI, 0.827-1). Supported vector machine modeling and partial least squares modeling were conducted to validate the predictive capabilities of the diagnostic panel. Metabolite profiling of TIO showed significant alterations compared with HC. A high-sensitivity and high-specificity panel with 5 oxylipins was tested as diagnostic predictor. For the first time, we provide the global profile of metabolomes and identify potential diagnostic biomarkers of TIO. The present work may offer novel insights into the pathogenesis of TIO.

OxyR-Like Improves Cell Hydrogen Peroxide Tolerance by Participating in Monocyte Chemotaxis and Oxidative Phosphorylation Regulation in Magnetospirillum Gryphiswaldense MSR-1.

The formation of magnetosomes inside magnetotactic bacteria is a complex process strictly controlled by the intracellular metabolic regulatory system. A series of transcriptional regulators are involved in the biosynthesis of the magnetosome, including OxyR-Like protein, which is indispensable for the maturation of magnetosomes in Magnetospirillum Gryphiswaldense MSR-1. In this study, a new function of the OxyR-Like protein that helps cells resist reactive oxygen species (ROS) was identified. A comparison of expression profile data between wild-type MSR-1 and an oxyR-Like defective mutant demonstrated that seven genes encoding chemotaxis proteins were down-regulated in the latter. On the contrary, the expression levels of numerous genes encoding proteins that are critical for cellular aerobic respiration were up-regulated. Thus, OxyR-Like enhanced the resistance of cells to ROS by increasing their environmental perception and maintaining their oxidative phosphorylation at a reasonable level to avoid the excessive production of endogenous ROS. These results increase our knowledge of the OxyR-Like regulatory network and establish a relationship between the antioxidant metabolic pathway and magnetosome biomineralization in MSR-1.

Multidimensional Single-Nuclei RNA-Seq Reconstruction of Adipose Tissue Reveals Adipocyte Plasticity Underlying Thermogenic Response.

Adipose tissue has been classified based on its morphology and function as white, brown, or beige/brite. It plays an essential role as a regulator of systemic metabolism through paracrine and endocrine signals. Recently, multiple adipocyte subtypes have been revealed using RNA sequencing technology, going beyond simply defined morphology but also by their cellular origin, adaptation to metabolic stress, and plasticity. Here, we performed an in-depth analysis of publicly available single-nuclei RNAseq from adipose tissue and utilized a workflow template to characterize adipocyte plasticity, heterogeneity, and secretome profiles. The reanalyzed dataset led to the identification of different subtypes of adipocytes including three subpopulations of thermogenic adipocytes, and provided a characterization of distinct transcriptional profiles along the adipocyte trajectory under thermogenic challenges. This study provides a useful resource for further investigations regarding mechanisms related to adipocyte plasticity and trans-differentiation.

Astrocyte Gliotransmission in the Regulation of Systemic Metabolism.

Normal brain function highly relies on the appropriate functioning of astrocytes. These glial cells are strategically situated between blood vessels and neurons, provide significant substrate support to neuronal demand, and are sensitive to neuronal activity and energy-related molecules. Astrocytes respond to many metabolic conditions and regulate a wide array of physiological processes, including cerebral vascular remodeling, glucose sensing, feeding, and circadian rhythms for the control of systemic metabolism and behavior-related responses. This regulation ultimately elicits counterregulatory mechanisms in order to couple whole-body energy availability with brain function. Therefore, understanding the role of astrocyte crosstalk with neighboring cells via the release of molecules, e.g., gliotransmitters, into the parenchyma in response to metabolic and neuronal cues is of fundamental relevance to elucidate the distinct roles of these glial cells in the neuroendocrine control of metabolism. Here, we review the mechanisms underlying astrocyte-released gliotransmitters that have been reported to be crucial for maintaining homeostatic regulation of systemic metabolism.

Cardiac-derived TGF-β1 confers resistance to diet-induced obesity through the regulation of adipocyte size and function

Regulation of organismal homeostasis in response to nutrient availability is a vital physiological process that involves inter-organ communication. Understanding the mechanisms controlling systemic cross-talk for the maintenance of metabolic health is critical to counteract diet-induced obesity. Here, we show that cardiac-derived transforming growth factor beta 1 (TGF-β1) protects against weight gain and glucose intolerance in mice subjected to high-fat diet. Secretion of TGF-β1 by cardiomyocytes correlates with the bioavailability of this factor in circulation. TGF-β1 prevents adipose tissue inflammation independent of body mass and glucose metabolism phenotypes, indicating protection from adipocyte dysfunction-driven immune cell recruitment. TGF-β1 alters the gene expression programs in white adipocytes, favoring their fatty acid oxidation and consequently increasing their mitochondrial oxygen consumption rates. Ultimately, subcutaneous and visceral white adipose tissue from cadiac-specific TGF-β1 transgenic mice fail to undergo cellular hypertrophy, leading to reduced overall adiposity during high-fat feeding. Thus, TGF-β1 is a critical mediator of heart-fat communication for the regulation of systemic metabolism.

Methylglyoxal attenuates isoproterenol-induced increase in uncoupling protein 1 expression through activation of JNK signaling pathway in beige adipocytes

Methylglyoxal (MG) is a metabolite derived from glycolysis whose levels in the blood and tissues of patients with diabetes are higher than those of healthy individuals, suggesting that MG is associated with the development of diabetic complications. However, it remains unknown whether high levels of MG are a cause or consequence of diabetes. Here, we show that MG negatively affects the expression of uncoupling protein 1 (UCP1), which is involved in thermogenesis and the regulation of systemic metabolism. Decreased Ucp1 expression is associated with obesity and type 2 diabetes. We found that MG attenuated the increase in Ucp1 expression following treatment with isoproterenol in beige adipocytes. However, MG did not affect protein kinase A signaling, the core coordinator of isoproterenol-induced Ucp1 expression. Instead, MG activated c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases. We found that JNK inhibition, but not p38, recovered isoproterenol-stimulated Ucp1 expression under MG treatment. Altogether, these results suggest an inhibitory role of MG on the thermogenic function of beige adipocytes through the JNK signaling pathway.

Exploring regulatory network of metabolism through liver research.

In recent years, the techniques in molecular biology have been dramatically advanced, and consequently the landscape of metabolism research has undergone a remarkable change. One of the emerging pictures as the fruits of these advancements is one depicting the regulation of systemic metabolism through inter-organ networks involving multiple tissues, either via humoral factors, which are secreted from one tissue and conveyed to their remote target tissues, or through neuronal networks which are integrated by the central nervous system. In addition, the progress in high-throughput research tools enabled detailed characterization and deeper understanding of the nature of human genome, which has attracted much attention to the importance of various non-coding RNAs species. These non-coding RNAs are often co-expressed and co-regulated with adjacent protein coding genes, adding higher levels of complexities by them functioning together as a system and often influencing biologically important pathways in a cooperative manner. Here in this review several examples of these regulatory network systems are presented, illustrating the significance of them in systemic metabolism, with a possible future research direction also being proposed.

Regulation of Systemic Metabolism by Autonomic Nerve-Mediated Inter-Organ Networks

Autonomic nerves, including sympathetic nerves and parasympathetic nerves, innervate organs and modulate those function, thereby regulating systemic metabolism. Autonomic nerve bundles contain both afferent and efferent nerve fibers, and both fibers play important roles in regulating systemic metabolism for maintenance of homeostasis at the whole-body level. Furthermore, recently-obtained evidence unraveled the metabolic regulatory systems through autonomic nerve-mediated inter-organ networks. In these systems, afferent innervations of autonomic nerves transmit metabolic information from peripheral organs to the central nervous system (CNS), and the CNS regulates organ functions based on the transmitted metabolic information through efferent innervations of autonomic nerves. In this review, autonomic nerve-mediated inter-organ networks that are involved in systemic metabolism are introduced, especially focusing on the liver-brain-pancreatic β-cell inter-organ network.

Leptin Improves Parameters of Brown Adipose Tissue Thermogenesis in Lipodystrophic Mice.

Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients.