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Nature Reviews. Endocrinology Feb 2023Traditional risk factors for obesity and the metabolic syndrome, such as excess energy intake and lack of physical activity, cannot fully explain the high prevalence of... (Review)
Review
Traditional risk factors for obesity and the metabolic syndrome, such as excess energy intake and lack of physical activity, cannot fully explain the high prevalence of these conditions. Insufficient sleep and circadian misalignment predispose individuals to poor metabolic health and promote weight gain and have received increased research attention in the past 10 years. Insufficient sleep is defined as sleeping less than recommended for health benefits, whereas circadian misalignment is defined as wakefulness and food intake occurring when the internal circadian system is promoting sleep. This Review discusses the impact of insufficient sleep and circadian misalignment in humans on appetite hormones (focusing on ghrelin, leptin and peptide-YY), energy expenditure, food intake and choice, and risk of obesity. Some potential strategies to reduce the adverse effects of sleep disruption on metabolic health are provided and future research priorities are highlighted. Millions of individuals worldwide do not obtain sufficient sleep for healthy metabolic functions. Furthermore, modern working patterns, lifestyles and technologies are often not conducive to adequate sleep at times when the internal physiological clock is promoting it (for example, late-night screen time, shift work and nocturnal social activities). Efforts are needed to highlight the importance of optimal sleep and circadian health in the maintenance of metabolic health and body weight regulation.
Topics: Humans; Sleep Deprivation; Circadian Rhythm; Sleep; Obesity; Weight Gain
PubMed: 36280789
DOI: 10.1038/s41574-022-00747-7 -
Biochemical Pharmacology May 2022Obesity is a chronic, relapsing condition characterized by excess body fat. Its prevalence has increased globally since the 1970s, and the number of obese and overweight... (Review)
Review
Obesity is a chronic, relapsing condition characterized by excess body fat. Its prevalence has increased globally since the 1970s, and the number of obese and overweight people is now greater than those underweight. Obesity is a multifactorial condition, and as such, many components contribute to its development and pathogenesis. This is the first of three companion reviews that consider obesity. This review focuses on the genetics, viruses, insulin resistance, inflammation, gut microbiome, and circadian rhythms that promote obesity, along with hormones, growth factors, and organs and tissues that control its development. It shows that the regulation of energy balance (intake vs. expenditure) relies on the interplay of a variety of hormones from adipose tissue, gastrointestinal tract, pancreas, liver, and brain. It details how integrating central neurotransmitters and peripheral metabolic signals (e.g., leptin, insulin, ghrelin, peptide YY) is essential for controlling energy homeostasis and feeding behavior. It describes the distinct types of adipocytes and how fat cell development is controlled by hormones and growth factors acting via a variety of receptors, including peroxisome proliferator-activated receptor-gamma, retinoid X, insulin, estrogen, androgen, glucocorticoid, thyroid hormone, liver X, constitutive androstane, pregnane X, farnesoid, and aryl hydrocarbon receptors. Finally, it demonstrates that obesity likely has origins in utero. Understanding these biochemical drivers of adiposity and metabolic dysfunction throughout the life cycle lends plausibility and credence to the "obesogen hypothesis" (i.e., the importance of environmental chemicals that disrupt these receptors to promote adiposity or alter metabolism), elucidated more fully in the two companion reviews.
Topics: Adipocytes; Adipose Tissue; Energy Metabolism; Humans; Insulin; Leptin; Obesity
PubMed: 35393120
DOI: 10.1016/j.bcp.2022.115012 -
International Journal of Molecular... Feb 2021Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease. The hypothesis that alterations in the microbiome are involved in the genesis of PCOS... (Review)
Review
Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease. The hypothesis that alterations in the microbiome are involved in the genesis of PCOS has been postulated. Aim of this review is to summarize the available literature data about the relationship between microbiome and PCOS. A search on PubMed and Medline databases was performed from inception to November 20Most of evidence has focused on the connection of intestinal bacteria with sex hormones and insulin-resistance: while in the first case, a relationship with hyperandrogenism has been described, although it is still unclear, in the second one, chronic low-grade inflammation by activating the immune system, with increased production of proinflammatory cytokines which interfere with insulin receptor function, causing IR (Insulin Resistance)/hyperinsulinemia has been described, as well as the role of gastrointestinal hormones like Ghrelin and peptide YY (PYY), bile acids, interleukin-22 and Bacteroides vulgatus have been highlighted. The lower genital tract microbiome would be affected by changes in PCOS patients too. The therapeutic opportunities include probiotic, prebiotics and synbiotics, as well as fecal microbiota transplantation and the use of IL-22, to date only in animal models, as a possible future drug. Current evidence has shown the involvement of the gut microbiome in PCOS, seen how humanized mice receiving a fecal transplant from women with PCOS develop ovarian dysfunction, immune changes and insulin resistance and how it is capable of disrupting the secondary bile acid biosynthesis. A future therapeutic approach for PCOS may involve the human administration of IL-22 and bile acid glycodeoxycholic acid.
Topics: Animals; Diet; Female; Gastrointestinal Microbiome; Genitalia, Female; Hormones; Humans; Insulin Resistance; Polycystic Ovary Syndrome
PubMed: 33669557
DOI: 10.3390/ijms22042048 -
Science (New York, N.Y.) Aug 2023The mammalian gut secretes a family of multifunctional peptides that affect appetite, intestinal secretions, and motility whereas others regulate the microbiota. We have...
The mammalian gut secretes a family of multifunctional peptides that affect appetite, intestinal secretions, and motility whereas others regulate the microbiota. We have found that peptide YY (PYY), but not endocrine PYY, acts as an antimicrobial peptide (AMP) expressed by gut epithelial paneth cells (PC). PC-PYY is packaged into secretory granules and is secreted into and retained by surface mucus, which optimizes PC-PYY activity. Although PC-PYY shows some antibacterial activity, it displays selective antifungal activity against virulent hyphae-but not the yeast form. PC-PYY is a cationic molecule that interacts with the anionic surfaces of fungal hyphae to cause membrane disruption and transcriptional reprogramming that selects for the yeast phenotype. Hence, PC-PYY is an antifungal AMP that contributes to the maintenance of gut fungal commensalism.
Topics: Animals; Antifungal Agents; Antimicrobial Peptides; Candida; Paneth Cells; Peptide Fragments; Peptide YY; Symbiosis; Humans; Mice
PubMed: 37535745
DOI: 10.1126/science.abq3178 -
Biomolecules Oct 2021Obesity is a highly prevalent public health concern, attributed to multifactorial causes and limited in treatment options. Several comorbidities are closely associated... (Review)
Review
Obesity is a highly prevalent public health concern, attributed to multifactorial causes and limited in treatment options. Several comorbidities are closely associated with obesity such as the development of type 2 diabetes mellitus (T2DM), cardiovascular and cerebrovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Bariatric surgery, which can be delivered in multiple forms, has been remarked as an effective treatment to decrease the prevalence of obesity and its associated comorbidities. The different types of bariatric surgery create a variety of new pathways for food to metabolize in the body and truncate the stomach's caliber. As a result, only a small quantity of food is tolerated, and the body mass index noticeably decreases. This review describes the improvements of obesity and its comorbidities following bariatric surgery and their mechanism of improvement. Additionally, endocrine function improvements after bariatric surgery, which contributes to the patients' health improvement, are described, including the role of glucagon-like peptide-1 (GLP-1), fibroblast growth factors 19 and 21 (FGF-19, FGF-21), and pancreatic peptide YY (PYY). Lastly, some of the complications of bariatric surgery, including osteoporosis, iron deficiency/anemia, and diarrhea, as well as their potential mechanisms, are described.
Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Humans; Iron Deficiencies
PubMed: 34827579
DOI: 10.3390/biom11111582 -
Cells Apr 2022Depression is a highly common mental disorder, which is often multifactorial with sex, genetic, environmental, and/or psychological causes. Recent advancements in... (Review)
Review
Depression is a highly common mental disorder, which is often multifactorial with sex, genetic, environmental, and/or psychological causes. Recent advancements in biomedical research have demonstrated a clear correlation between gut dysbiosis (GD) or gut microbial dysbiosis and the development of anxiety or depressive behaviors. The gut microbiome communicates with the brain through the neural, immune, and metabolic pathways, either directly (via vagal nerves) or indirectly (via gut- and microbial-derived metabolites as well as gut hormones and endocrine peptides, including peptide YY, pancreatic polypeptide, neuropeptide Y, cholecystokinin, corticotropin-releasing factor, glucagon-like peptide, oxytocin, and ghrelin). Maintaining healthy gut microbiota (GM) is now being recognized as important for brain health through the use of probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), etc. A few approaches exert antidepressant effects via restoring GM and hypothalamus-pituitary-adrenal (HPA) axis functions. In this review, we have summarized the etiopathogenic link between gut dysbiosis and depression with preclinical and clinical evidence. In addition, we have collated information on the recent therapies and supplements, such as probiotics, prebiotics, short-chain fatty acids, and vitamin B12, omega-3 fatty acids, etc., which target the gut-brain axis (GBA) for the effective management of depressive behavior and anxiety.
Topics: Depression; Depressive Disorder, Major; Dysbiosis; Humans; Prebiotics; Synbiotics
PubMed: 35456041
DOI: 10.3390/cells11081362 -
Molecular and Cellular Endocrinology Nov 2019The pathophysiology of anorexia nervosa (AN) and bulimia nervosa (BN) are still poorly understood, but psychobiological models have proposed a key role for disturbances... (Review)
Review
The pathophysiology of anorexia nervosa (AN) and bulimia nervosa (BN) are still poorly understood, but psychobiological models have proposed a key role for disturbances in the neuroendocrines that signal hunger and satiety and maintain energy homeostasis. Mounting evidence suggests that many neuroendocrines involved in the regulation of homeostasis and body weight also play integral roles in food reward valuation and learning via their interactions with the mesolimbic dopamine system. Neuroimaging data have associated altered brain reward responses in this system with the dietary restriction and binge eating and purging characteristic of AN and BN. Thus, neuroendocrine dysfunction may contribute to or perpetuate eating disorder symptoms via effects on reward circuitry. This narrative review focuses on reward-related neuroendocrines that are altered in eating disorder populations, including peptide YY, insulin, stress and gonadal hormones, and orexins. We provide an overview of the animal and human literature implicating these neuroendocrines in dopaminergic reward processes and discuss their potential relevance to eating disorder symptomatology and treatment.
Topics: Animals; Anorexia Nervosa; Bulimia Nervosa; Ghrelin; Humans; Leptin; Neuroendocrinology; Reward
PubMed: 30395874
DOI: 10.1016/j.mce.2018.10.018 -
Journal of Obesity & Metabolic Syndrome Jun 2022Regulation of appetite is dependent on crosstalk between the gut and the brain, which is a pathway described as the gut-brain axis (GBA). Three primary... (Review)
Review
Regulation of appetite is dependent on crosstalk between the gut and the brain, which is a pathway described as the gut-brain axis (GBA). Three primary appetite-regulating hormones that are secreted in the gut as a response to eating a meal are glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), and peptide YY (PYY). When these hormones are secreted, the GBA responds to reduce appetite. However, secretion of these hormones and the response of the GBA can vary depending on the types of nutrients consumed. This narrative review describes how the gut secretes GLP-1, CCK, and PYY in response to proteins, carbohydrates, and fats. In addition, the GBA response based on the quality of the meal is described in the context of which meal types produce greater appetite suppression. Last, the beneficiary role of exercise as a mediator of appetite regulation is highlighted.
PubMed: 35718856
DOI: 10.7570/jomes22031 -
Journal of Hematology & Oncology Oct 2022Non-inflamed tumors, including immune-excluded and immune-desert tumors, are commonly resistant to anti-PD-1/PD-L1 (α-PD-1/PD-L1) therapy. Our previous study reported...
BACKGROUND
Non-inflamed tumors, including immune-excluded and immune-desert tumors, are commonly resistant to anti-PD-1/PD-L1 (α-PD-1/PD-L1) therapy. Our previous study reported the potent antitumor activity of anti-TGF-β/PD-L1 bispecific antibody YM101 in immune-excluded tumors. However, YM101 had limited antitumor activity in immune-desert models. MSA-2 is a novel oral stimulator of interferon genes (STING) agonist, which activates the innate immune system and may synergize with YM101 in overcoming immunotherapy resistance.
METHODS
The dose-dependent effect of MSA-2 on STING signaling was determined by interferon-β level. The maturation and function of dendritic cell (DC) were measured by flow cytometry, RNA-seq, one-way mixed lymphocyte reaction (MLR), OVA peptide pulse, and cytokine/chemokine detection. The synergistic effect between MSA-2 and YM101 was assessed by one-way MLR. The macrophage activation was measured by flow cytometry and cytokine/chemokine detection. The in vivo antitumor activity of MSA-2 combined with YM101 was explored in syngeneic murine tumor models. After treatments, the alterations in the tumor microenvironment (TME) were detected by flow cytometry, immunohistochemistry staining, immunofluorescence staining, RNA-seq, and single-cell RNA-seq (scRNA-seq).
RESULTS
MSA-2 could promote the maturation and antigen presentation capability of murine DC. In the one-way MLR assay, MSA-2 synergized with YM101 in enhancing naive T cell activation. Moreover, MSA-2 stimulated the classical activation of macrophage, without significant influence on alternative activation. Further in vivo explorations showed that MSA-2 increased multiple proinflammatory cytokines and chemokines in the TME. MSA-2 combined with YM101 remarkedly retarded tumor growth in immune-excluded and immune-desert models, with superior antitumor activity to monotherapies. Flow cytometry, bulk RNA-seq, and scRNA-seq assays indicated that the combination therapy simultaneously boosted the innate and adaptive immunity, promoted antigen presentation, improved T cell migration and chemotaxis, and upregulated the numbers and activities of tumor-infiltrating lymphocytes.
CONCLUSION
Our results demonstrate that MSA-2 synergizes with YM101 in boosting antitumor immunity. This immune cocktail therapy effectively overcomes immunotherapy resistance in immune-excluded and immune-desert models.
Topics: Animals; Antibodies, Bispecific; B7-H1 Antigen; Cell Line, Tumor; Cytokines; Humans; Immunotherapy; Interferon-beta; Interferons; Membrane Proteins; Mice; Neoplasms; Transforming Growth Factor beta; Tumor Microenvironment
PubMed: 36209176
DOI: 10.1186/s13045-022-01363-8 -
Circulation Oct 2020Heart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene... (Clinical Trial)
Clinical Trial
BACKGROUND
Heart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene expression may identify new candidates for biomarker and drug target discovery.
METHODS
We used aptamer-based affinity-capture plasma proteomics to measure 1305 plasma proteins at 1 month post-MI in a New Zealand cohort (CDCS [Coronary Disease Cohort Study]) including 181 patients post-MI who were subsequently hospitalized for HF in comparison with 250 patients post-MI who remained event free over a median follow-up of 4.9 years. We then correlated plasma proteins with left ventricular ejection fraction measured at 4 months post-MI and identified proteins potentially coregulated in post-MI HF using weighted gene co-expression network analysis. A Singapore cohort (IMMACULATE [Improving Outcomes in Myocardial Infarction through Reversal of Cardiac Remodelling]) of 223 patients post-MI, of which 33 patients were hospitalized for HF (median follow-up, 2.0 years), was used for further candidate enrichment of plasma proteins by using Fisher meta-analysis, resampling-based statistical testing, and machine learning. We then cross-referenced differentially expressed proteins with their differentially expressed genes from single-cell transcriptomes of nonmyocyte cardiac cells isolated from a murine MI model, and single-cell and single-nucleus transcriptomes of cardiac myocytes from murine HF models and human patients with HF.
RESULTS
In the CDCS cohort, 212 differentially expressed plasma proteins were significantly associated with subsequent HF events. Of these, 96 correlated with left ventricular ejection fraction measured at 4 months post-MI. Weighted gene co-expression network analysis prioritized 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF in comparison with event-free controls (data set 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (data set 2), whereas single-cell transcriptomes identified 15 gene-protein candidates (data set 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly enriched proteins that were common to all 3 data sets included well-established biomarkers of post-MI HF: N-terminal B-type natriuretic peptide and troponin T, and newly emergent biomarkers, angiopoietin-2, thrombospondin-2, latent transforming growth factor-β binding protein-4, and follistatin-related protein-3, as well.
CONCLUSIONS
Large-scale human plasma proteomics, cross-referenced to unbiased cardiac transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation.
Topics: Aged; Aged, 80 and over; Animals; Blood Proteins; Female; Gene Expression Profiling; Gene Expression Regulation; Heart Failure; Humans; Male; Mice; Middle Aged; Myocardial Infarction; Proteomics; Single-Cell Analysis
PubMed: 32885678
DOI: 10.1161/CIRCULATIONAHA.119.045158