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Background: Inflammatory processes are a cause of accelerated loss of muscle mass. Metabolic syndrome (MetS) is a highly prevalent age-related condition, which may promote and be promoted by inflammation. However, whether inflammation in MetS (metaflammation) is associated with lower muscle mass is still unclear. Methods: Complete cross-sectional data on body composition, MetS, and the inflammatory markers interleukin (IL)-1 beta, IL-6, IL-10, tumor necrosis factor (TNF), and C-reactive protein (CRP) were available for 1,377 BASE-II participants (51.1% women; 68 +/- 4 years old). Appendicular lean mass (ALM) was assessed by dual-energy X-ray absorptiometry. Low muscle mass (low ALM-to-BMI ratio [ALMBMI]) was defined according to the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project. Regression models, adjusted for an increasing number of confounders (sex, age, physical activity, morbidities, diabetes mellitus type II, TSH, albumin, HbA1c, smoking habits, alcohol intake, education, and energy intake/day), were used to calculate the association between low ALMBMI and high inflammation (tertile 3) according to MetS. Results: MetS was present in 36.2% of the study population, and 9% had low ALMBMI. In the whole study population, high CRP (odds ratio [OR]: 2.7 [95% CI: 1.6-4.7; p = 0.001]) and high IL-6 (OR: 2.1 [95% CI: 1.2-1.9; p = 0.005]) were associated with low ALMBMI. In contrast, no significant association was found between TNF, IL-10, or IL-1 beta with low ALMBMI. When participants were stratified by MetS, results for IL-6 remained significant only in participants with MetS. Conclusions: Among BASE-II participants, low ALMBMI was associated with inflammation. Low-grade inflammation triggered by disease state, especially in the context of MetS, might favor loss of muscle mass, so a better control of MetS might help to prevent sarcopenia. Intervention studies to test whether strategies to prevent MetS might also prevent loss of muscle mass seem to be promising.
The ever-increasing fat content in Western diet, combined with decreased levels of physical activity, greatly enhance the incidence of metabolic-related diseases. Cancer cachexia (CC) and Metabolic syndrome (MetS) are both multifactorial highly complex metabolism related syndromes, whose etiology is not fully understood, as the mechanisms underlying their development are not completely unveiled. Nevertheless, despite being considered “opposite sides”, MetS and CC share several common issues such as insulin resistance and low-grade inflammation. In these scenarios, tissue macrophages act as key players, due to their capacity to produce and release inflammatory mediators. One of the main features of MetS is hyperinsulinemia, which is generally associated with an attempt of the β-cell to compensate for diminished insulin sensitivity (insulin resistance). There is growing evidence that hyperinsulinemia per se may contribute to the development of insulin resistance, through the establishment of low grade inflammation in insulin responsive tissues, especially in the liver (as insulin is secreted by the pancreas into the portal circulation). The hypothesis of the present study was that insulin may itself provoke an inflammatory response culminating in diminished hepatic insulin sensitivity. To address this premise, firstly, human cell line U937 differentiated macrophages were exposed to insulin, LPS and PGE2. In these cells, insulin significantly augmented the gene expression of the pro-inflammatory mediators IL-1β, IL-8, CCL2, Oncostatin M (OSM) and microsomal prostaglandin E2 synthase (mPGES1), and of the anti-inflammatory mediator IL-10. Moreover, the synergism between insulin and LPS enhanced the induction provoked by LPS in IL-1β, IL-8, IL-6, CCL2 and TNF-α gene. When combined with PGE2, insulin enhanced the induction provoked by PGE2 in IL-1β, mPGES1 and COX2, and attenuated the inhibition induced by PGE2 in CCL2 and TNF-α gene expression contributing to an enhanced inflammatory response by both mechanisms. Supernatants of insulin-treated U937 macrophages reduced the insulin-dependent induction of glucokinase in hepatocytes by 50%. Cytokines contained in the supernatant of insulin-treated U937 macrophages also activated hepatocytes ERK1/2, resulting in inhibitory serine phosphorylation of the insulin receptor substrate. Additionally, the transcription factor STAT3 was activated by phosphorylation resulting in the induction of SOCS3, which is capable of interrupting the insulin receptor signal chain. MicroRNAs, non-coding RNAs linked to protein expression regulation, nowadays recognized as active players in the generation of several inflammatory disorders such as cancer and type II diabetes are also of interest. Considering that in cancer cachexia, patients are highly affected by insulin resistance and inflammation, control, non-cachectic and cachectic cancer patients were selected and the respective circulating levels of pro-inflammatory mediators and microRNA-21-5p, a posttranscriptional regulator of STAT3 expression, assessed and correlated. Cachectic patients circulating cytokines IL-6 and IL-8 levels were significantly higher than those of non-cachectic and controls, and the expression of microRNA-21-5p was significantly lower. Additionally, microRNA-21-5p reduced expression correlated negatively with IL-6 plasma levels. These results indicate that hyperinsulinemia per se might contribute to the low grade inflammation prevailing in MetS patients and thereby promote the development
of insulin resistance particularly in the liver. Diminished MicroRNA-21-5p expression may enhance inflammation and STAT3 expression in cachectic patients, contributing to the development of insulin resistance.
Das Metabolische Syndrom stellt eine Kombination verschiedener metabolischer Anomalien in einem Individuum dar. Starkes Übergewicht gilt als maßgebende Größe in der Genese des Syndroms, welches mit einem enormen Risiko für kardiovaskuläre Erkrankungen einhergeht. Um die stark steigende Prävalenz des Metabolischen Syndroms einzudämmen, sind dringend Konzepte für die Behandlung, vor allem jedoch für die Prävention von Übergewicht erforderlich. Einen wichtigen Beitrag leisten diesbezüglich Ballaststoffe in der Ernährung. Sie tragen auf unterschiedlichen Wegen zur Gewichtskontrolle bei und beeinflussen zudem verschiedene mit dem Metabolischen Syndrom assoziierte Blutparameter. Ebenso werden protektive Effekte von Polyphenolen, welche zur Gruppe der sekundären Pflanzenstoffe zählen, beschrieben. Diese wirken u. a. auf den Glukose- sowie den Insulinhaushalt und greifen darüber hinaus in die Regulation der Fettverbrennung sowie des Energieverbrauches ein. Die Kombination beider Substanzgruppen verspricht bedeutendes gesundheitsförderndes Potential; dieses wurde gegenwärtig jedoch kaum untersucht. Carobballaststoff ist ein polyphenolreicher und vorwiegend unlöslicher Extrakt der Frucht des Johannisbrotbaumes (Ceratonia siliqua L). Bislang publizierte Studien zur physiologischen Wirksamkeit dieses Ballaststoffpräparates weisen sowohl beim Tier als auch beim Menschen bemerkenswerte hypocholesterinämische Eigenschaften nach. Inwiefern sich der Verzehr des Carobballaststoffes ebenso auf die Entwicklung von Übergewicht sowie anderen Messgrößen des Metabolischen Syndroms auswirkt, ist allerdings nicht bekannt. Die Zielstellung der Promotionsarbeit bestand darin, die postprandialen Wirkungen des Carobballaststoffverzehrs mit Hilfe einer Humanstudie aufzuzeigen. In die randomisierten, einfach verblindeten Untersuchungen im cross-over-Design wurden 20 gesunde Erwachsene im Alter zwischen 22 und 62 Jahren eingeschlossen. Unter Verwendung variierender Begleitmahlzeiten wurden die postprandialen Effekte verschiedener Mengen des Carobballaststoffes untersucht. Hierbei standen die Veränderungen der Plasmakonzentrationen von Glukose, Triglyceriden (TG), totalem und acyliertem Ghrelin sowie der Serumkonzentrationen von Insulin und nicht-veresterten Fettsäuren (NEFA) im Mittelpunkt der Betrachtungen. Der Verzehr des Carobballaststoffes in Kombination mit 200 ml Wasser und 50 g Glukose erhöhte die postprandialen Glukose- und Insulinkonzentrationen gegenüber der Glukoselösung ohne Ballaststoffzusatz. In Kombination mit 400 ml einer Flüssigmahlzeit verzehrt, senkte Carobballaststoff die postprandialen TG-, NEFA- und Ghrelin- (acyliert) Antworten. Die Untersuchung des respiratorischen Quotienten nach Zusatz von Carobballaststoff zur Flüssigmahlzeit mittels indirekter Respirationskalorimetrie bekräftigte die bereits bekannten Effekte auf den Lipidmetabolismus und wies zudem eine Steigerung der Fettverwertung unter Verminderung der Glukoseoxidation nach. Wurde Carobballaststoff schließlich in Lebensmittel eingebracht, sanken nach dem Verzehr dieser Lebensmittel erneut die postprandialen Konzentrationen an TG und NEFA. Gleichzeitig erhöhten sich die Glukose-, Insulin- sowie Ghrelin- (acyliert) Antworten. Carobballaststoff löst in Abhängigkeit von der jeweils verzehrten Begleitmatrix unterschiedliche Effekte aus. Das Präparat weist beachtliche Wirkungen auf die Blutlipide sowie den Energieverbrauch auf, hat indes ungünstige Wirkungen auf die Blutglukose, sofern er in Kombination mit einer veränderten Nährstoffmatrix aufgenommen wird. Carobballaststoff besitzt starkes gesundheitsförderndes Potential; jedoch sind weitere Studien notwendig, um seine Wirkungen sowie deren Voraussetzungen besser zu verstehen. Ferner sollten Untersuchungen über einen längeren Zeitraum vorgenommen werden, um die langfristige Relevanz der gewonnenen Ergebnisse darzulegen. Danach stellt die Anreicherung spezieller Lebensmittel mit Carobballaststoff einen geeigneten Weg dar, um von den viel versprechenden protektiven Wirkungen des Präparates zu profitieren.
Aim: To investigate the relationship of vitamin D-binding protein (GC) and genetic variation of GC (rs4588, rs7041 and rs2282679) with metabolic syndrome (MetS) in the Thai population. Materials & methods: GCglobulin concentrations were measured by quantitative western blot analysis in 401 adults. All participants were genotyped using TaqMan allelic discrimination assays. Results: GC-globulin levels were significatly lower in MetS subjects than in control subjects, in which significant negative correlations of GC-globulin levels with systolic blood pressure, glucose and age were found. Male participants who carried the GT genotype for rs4588 showed an increased risk of MetS compared with the GG wild-type (odds ratio: 3.25; p = 0.004). Conclusion: GC-globulin concentrations and variation in GC rs4588 were supported as a risk factor for MetS in Thais.
As a tumor suppressor and the most frequently mutated gene in cancer, p53 is among the best-described molecules in medical research. As cancer is in most cases an age-related disease, it seems paradoxical that p53 is so strongly conserved from early multicellular organisms to humans. A function not directly related to tumor suppression, such as the regulation of metabolism in nontransformed cells, could explain this selective pressure. While this role of p53 in cellular metabolism is gradually emerging, it is imperative to dissect the tissue-and cell-specific actions of p53 and its downstream signaling pathways. In this review, we focus on studies reporting p53's impact on adipocyte development, function, and maintenance, as well as the causes and consequences of altered p53 levels in white and brown adipose tissue (AT) with respect to systemic energy homeostasis. While whole body p53 knockout mice gain less weight and fat mass under a high-fat diet owing to increased energy expenditure, modifying p53 expression specifically in adipocytes yields more refined insights: (1) p53 is a negative regulator of in vitro adipogenesis; (2) p53 levels in white AT are increased in diet-induced and genetic obesity mouse models and in obese humans; (3) functionally, elevated p53 in white AT increases senescence and chronic inflammation, aggravating systemic insulin resistance; (4) p53 is not required for normal development of brown AT; and (5) when p53 is activated in brown AT in mice fed a high-fat diet, it increases brown AT temperature and brown AT marker gene expression, thereby contributing to reduced fat mass accumulation. In addition, p53 is increasingly being recognized as crucial player in nutrient sensing pathways. Hence, despite existence of contradictory findings and a varying density of evidence, several functions of p53 in adipocytes and ATs have been emerging, positioning p53 as an essential regulatory hub in ATs. Future studies need to make use of more sophisticated in vivo model systems and should identify an AT-specific set of p53 target genes and downstream pathways upon different (nutrient) challenges to identify novel therapeutic targets to curb metabolic diseases
As a tumor suppressor and the most frequently mutated gene in cancer, p53 is among the best-described molecules in medical research. As cancer is in most cases an age-related disease, it seems paradoxical that p53 is so strongly conserved from early multicellular organisms to humans. A function not directly related to tumor suppression, such as the regulation of metabolism in nontransformed cells, could explain this selective pressure. While this role of p53 in cellular metabolism is gradually emerging, it is imperative to dissect the tissue-and cell-specific actions of p53 and its downstream signaling pathways. In this review, we focus on studies reporting p53's impact on adipocyte development, function, and maintenance, as well as the causes and consequences of altered p53 levels in white and brown adipose tissue (AT) with respect to systemic energy homeostasis. While whole body p53 knockout mice gain less weight and fat mass under a high-fat diet owing to increased energy expenditure, modifying p53 expression specifically in adipocytes yields more refined insights: (1) p53 is a negative regulator of in vitro adipogenesis; (2) p53 levels in white AT are increased in diet-induced and genetic obesity mouse models and in obese humans; (3) functionally, elevated p53 in white AT increases senescence and chronic inflammation, aggravating systemic insulin resistance; (4) p53 is not required for normal development of brown AT; and (5) when p53 is activated in brown AT in mice fed a high-fat diet, it increases brown AT temperature and brown AT marker gene expression, thereby contributing to reduced fat mass accumulation. In addition, p53 is increasingly being recognized as crucial player in nutrient sensing pathways. Hence, despite existence of contradictory findings and a varying density of evidence, several functions of p53 in adipocytes and ATs have been emerging, positioning p53 as an essential regulatory hub in ATs. Future studies need to make use of more sophisticated in vivo model systems and should identify an AT-specific set of p53 target genes and downstream pathways upon different (nutrient) challenges to identify novel therapeutic targets to curb metabolic diseases.
Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the beta-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1 beta, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1 beta was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-kappa B. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKK beta, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues.
Association of primary allostatic load mediators and metabolic syndrome (MetS): A systematic review
(2022)
Allostatic load (AL) exposure may cause detrimental effects on the neuroendocrine system, leading to metabolic syndrome (MetS). The primary mediators of AL involve serum dehydroepiandrosterone sulfate (DHEAS; a functional HPA axis antagonist); further, cortisol, urinary norepinephrine (NE), and epinephrine (EPI) excretion levels (assessed within 12-h urine as a golden standard for the evaluation of the HPA axis activity and sympathetic nervous system activity). However, the evidence of an association between the primary mediators of AL and MetS is limited. This systematic review aimed to critically examine the association between the primary mediators of AL and MetS. PubMed and Web of Science were searched for articles from January 2010 to December 2021, published in English. The search strategy focused on cross-sectional and case–control studies comprising adult participants with MetS, obesity, overweight, and without chronic diseases. The STROBE checklist was used to assess study quality control. Of 770 studies, twenty-one studies with a total sample size (n = 10,666) met the eligibility criteria. Eighteen studies were cross-sectional, and three were case–control studies. The included studies had a completeness of reporting score of COR % = 87.0 ± 6.4%. It is to be noted, that cortisol as a primary mediator of AL showed an association with MetS in 50% (urinary cortisol), 40% (serum cortisol), 60% (salivary cortisol), and 100% (hair cortisol) of the studies. For DHEAS, it is to conclude that 60% of the studies showed an association with MetS. In contrast, urinary EPI and urinary NE had 100% no association with MetS. In summary, there is a tendency for the association between higher serum cortisol, salivary cortisol, urinary cortisol, hair cortisol, and lower levels of DHEAS with MetS. Future studies focusing on longitudinal data are warranted for clarification and understanding of the association between the primary mediators of AL and MetS.
Association of primary allostatic load mediators and metabolic syndrome (MetS): A systematic review
(2022)
Allostatic load (AL) exposure may cause detrimental effects on the neuroendocrine system, leading to metabolic syndrome (MetS). The primary mediators of AL involve serum dehydroepiandrosterone sulfate (DHEAS; a functional HPA axis antagonist); further, cortisol, urinary norepinephrine (NE), and epinephrine (EPI) excretion levels (assessed within 12-h urine as a golden standard for the evaluation of the HPA axis activity and sympathetic nervous system activity). However, the evidence of an association between the primary mediators of AL and MetS is limited. This systematic review aimed to critically examine the association between the primary mediators of AL and MetS. PubMed and Web of Science were searched for articles from January 2010 to December 2021, published in English. The search strategy focused on cross-sectional and case–control studies comprising adult participants with MetS, obesity, overweight, and without chronic diseases. The STROBE checklist was used to assess study quality control. Of 770 studies, twenty-one studies with a total sample size (n = 10,666) met the eligibility criteria. Eighteen studies were cross-sectional, and three were case–control studies. The included studies had a completeness of reporting score of COR % = 87.0 ± 6.4%. It is to be noted, that cortisol as a primary mediator of AL showed an association with MetS in 50% (urinary cortisol), 40% (serum cortisol), 60% (salivary cortisol), and 100% (hair cortisol) of the studies. For DHEAS, it is to conclude that 60% of the studies showed an association with MetS. In contrast, urinary EPI and urinary NE had 100% no association with MetS. In summary, there is a tendency for the association between higher serum cortisol, salivary cortisol, urinary cortisol, hair cortisol, and lower levels of DHEAS with MetS. Future studies focusing on longitudinal data are warranted for clarification and understanding of the association between the primary mediators of AL and MetS.
Übergewicht, Diabetes oder Fettstoffwechselstörungen sind mit erniedrigten Adiponectinspiegeln assoziiert. Eine Modulation des Adiponectins kann durch genetische und metabolische Gegebenheiten erfolgen. Das Ziel dieser Arbeit war die Analyse von Faktoren, welche die Adiponectinspiegel beeinflussen können, sowie eine Charakterisierung der Oligomerverteilung unter verschiedenen metabolischen Bedingungen. In der MeSyBePo-Kohorte waren die zirkulierenden Adiponectinspiegel mit den Promotorpolymorphismen ADIPOQ -11377 C/G und ADIPOQ -11391 G/A im Adiponectingen assoziiert. Im Hinblick auf die metabolischen Faktoren korrelierte Adiponectin eng mit Parametern des Glukose- und Fettstoffwechsels sowie dem Übergewicht. Innerhalb von hyperinsulinämischen euglykämischen Clamps führte eine akute Hyperinsulinämie zu einer Abnahme der Adiponectinspiegel. Adiponectin zirkuliert im Serum als hochmolekulare (HMW), mittelmolekulare (MMW) und niedrigmolekulare (LMW) Spezies. Mit zunehmendem Körpergewicht konnte eine Verlagerung von HMW-Spezies hin zu den LMW-Spezies beobachtet werden. Durch eine moderate Gewichtsabnahme erhöhten sich die Anteile an HMW- und MMW-Adiponectin wieder. Während sich in Abhängigkeit vom Glukosemetabolismus keine Unterschiede in den Gesamtspiegeln ergaben, wurden bei Personen mit normaler Glukosetoleranz signifikant höhere Anteile an MMW-Adiponectin detektiert als bei Personen mit einem gestörten Glukosestoffwechsel. Insgesamt scheinen die HMW- und MMW-Spezies gegensätzlich zur LMW-Spezies reguliert zu werden. Die Arbeit unterstreicht die wichtige Rolle des Adiponectins im Glukose- und Fettstoffwechsel sowie bei einer Adipositas in vivo. Dabei waren Änderungen der Adiponectinspiegel bei Vorliegen von Insulinresistenz und Adipositas stets mit einer Umverteilung der Oligomerfraktionen verbunden. Vor allem die HMW- und MMW-Spezies des Adiponectins scheinen von entscheidender Bedeutung zu sein.