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The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet-induced (HFD-induced) obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked CR's effects on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction. Mechanistically, SPARC activates the NLRP3 inflammasome at the priming step and downregulation of SPARC lowers macrophage inflammation in adipose tissue, while excess SPARC activated macrophages via JNK signaling. Collectively, reduction of adipocyte-derived SPARC confers CR-like metabolic and antiinflammatory benefits in obesity by serving as an immunometabolic checkpoint of inflammation.

The extension of life span driven by 40% caloric restriction (CR) in rodents causes trade-offs in growth, reproduction, and immune defense that make it difficult to identify therapeutically relevant CR-mimetic targets. We report that about 14% CR for 2 years in healthy humans improved thymopoiesis and was correlated with mobilization of intrathymic ectopic lipid. CR-induced transcriptional reprogramming in adipose tissue implicated pathways regulating mitochondrial bioenergetics, anti-inflammatory responses, and longevity. Expression of the gene Pla2g7 encoding platelet activating factor acetyl hydrolase (PLA2G7) is inhibited in humans undergoing CR. Deletion of Pla2g7 in mice showed decreased thymic lipoatrophy, protection against age-related inflammation, lowered NLRP3 inflammasome activation, and improved metabolic health. Therefore, the reduction of PLA2G7 may mediate the immunometabolic effects of CR and could potentially be harnessed to lower inflammation and extend the health span.

Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes 1,2 . Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized 3-6 . Here we define a critical role of IL-27-IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK-PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

During aging, visceral adiposity is often associated with alterations in adipose tissue (AT) leukocytes, inflammation, and metabolic dysfunction. However, the contribution of AT B cells in immunometabolism during aging is unexplored. Here, we show that aging is associated with an expansion of a unique population of resident non-senescent aged adipose B cells (AABs) found in fat-associated lymphoid clusters (FALCs). AABs are transcriptionally distinct from splenic age-associated B cells (ABCs) and show greater expansion in female mice. Functionally, whole-body B cell depletion restores proper lipolysis and core body temperature maintenance during cold stress. Mechanistically, the age-induced FALC formation, AAB, and splenic ABC expansion is dependent on the Nlrp3 inflammasome. Furthermore, AABs express IL-1R, and inhibition of IL-1 signaling reduces their proliferation and increases lipolysis in aging. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging AT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The role of the immune system in homeostasis of pancreatic β cells in type 2 diabetes mellitus is poorly characterized. In a recent issue of Cell Metabolism, Ying et al. (2018) report that two subpopulations of macrophages expand during obesity to impair β cell function., (Copyright © 2018. Published by Elsevier Inc.)

DNAJC17 is a heat shock protein (HSP40) family member, identified in mouse as susceptibility gene for congenital hypothyroidism. DNAJC17 knockout mouse embryos die prior to implantation. In humans, germline homozygous mutations in DNAJC17 have been found in syndromic retinal dystrophy patients, while heterozygous mutations represent candidate pathogenic events for myeloproliferative disorders. Despite widespread expression and involvement in human diseases, DNAJC17 function is still poorly understood. Herein, we have investigated its function through high-throughput transcriptomic and proteomic approaches. DNAJC17-depleted cells transcriptome highlighted genes involved in general functional categories, mainly related to gene expression. Conversely, DNAJC17 interactome can be classified in very specific functional networks, with the most enriched one including proteins involved in splicing. Furthermore, several splicing-related interactors, were independently validated by co-immunoprecipitation and in vivo co-localization. Accordingly, co-localization of DNAJC17 with SC35, a marker of nuclear speckles, further supported its interaction with spliceosomal components. Lastly, DNAJC17 up-regulation enhanced splicing efficiency of minigene reporter in live cells, while its knockdown induced perturbations of splicing efficiency at whole genome level, as demonstrated by specific analysis of RNAseq data. In conclusion, our study strongly suggests a role of DNAJC17 in splicing-related processes and provides support to its recognized essential function in early development.

Hypothyroidism, a metabolic disease characterized by low thyroid hormone (TH) and high thyroid-stimulating hormone (TSH) levels in the serum, is strongly associated with nonalcoholic fatty liver disease (NAFLD). Hypothyroidism-induced NAFLD has generally been attributed to reduced TH signaling in the liver with a consequent decrease in lipid utilization. Here, we found that mildly hypothyroid mice develop NAFLD without down-regulation of hepatic TH signaling or decreased hepatic lipid utilization. NAFLD was induced by impaired suppression of adipose tissue lipolysis due to decreased insulin secretion and to a reduced response of adipose tissue itself to insulin. This condition leads to increased shuttling of fatty acids (FAs) to the liver, where they are esterified and accumulated as triglycerides. Lipid accumulation in the liver induces hepatic insulin resistance, which leads to impaired suppression of endogenous glucose production after feeding. Hepatic insulin resistance, synergistically with lowered insulin secretion, increases serum glucose levels, which stimulates de novo lipogenesis (DNL) in the liver. Up-regulation of DNL also contributes to NAFLD. In contrast, severely hypothyroid mice show down-regulation of TH signaling in their livers and profound suppression of adipose tissue lipolysis, which decreases delivery of FAs to the liver. The resulting lack of substrates for triglyceride esterification protects severely hypothyroid mice against NAFLD. Our findings demonstrate that NAFLD occurs when TH levels are mildly reduced, but, paradoxically, not when they are severely reduced. Our results show that the pathogenesis of hypothyroidism-induced NAFLD is both intra- and extrahepatic; they also reveal key metabolic differences between mild and severe hypothyroidism., Competing Interests: The authors declare no conflict of interest., (Published under the PNAS license.)

Catecholamine-induced lipolysis, the first step in the generation of energy substrates by the hydrolysis of triglycerides, declines with age. The defect in the mobilization of free fatty acids in the elderly is accompanied by increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. Although catecholamine signalling in adipocytes is normal in the elderly, how lipolysis is impaired in ageing remains unknown. Here we show that adipose tissue macrophages regulate the age-related reduction in adipocyte lipolysis in mice by lowering the bioavailability of noradrenaline. Unexpectedly, unbiased whole-transcriptome analyses of adipose macrophages revealed that ageing upregulates genes that control catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in ageing restored catecholamine-induced lipolysis by downregulating growth differentiation factor-3 (GDF3) and monoamine oxidase A (MAOA) that is known to degrade noradrenaline. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing levels of MAOA and caspase-1. Furthermore, inhibition of MAOA reversed the age-related reduction in noradrenaline concentration in adipose tissue, and restored lipolysis with increased levels of the key lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-immunometabolic signalling between the sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.

In concert with their phagocytic activity, macrophages are thought to regulate the host immunometabolic responses primarily via their ability to produce specific cytokines and metabolites. Here, we show that IL-4-differentiated, M2-like macrophages secrete IGF1, a hormone previously thought to be exclusively produced from liver. Ablation of IGF1 receptors from myeloid cells reduced phagocytosis, increased macrophages in adipose tissue, elevated adiposity, lowered energy expenditure, and led to insulin resistance in mice fed a high-fat diet. The investigation of adipose macrophage phenotype in obese myeloid IGF1R knockout (MIKO) mice revealed a reduction in transcripts associated with M2-like macrophage activation. Furthermore, the MIKO mice infected with helminth Nippostrongylus brasiliensis displayed delayed resolution from infection with normal insulin sensitivity. Surprisingly, cold challenge did not trigger an overt M2-like state and failed to induce tyrosine hydroxylase expression in adipose tissue macrophages of control or MIKO mice. These results show that IGF1 signaling shapes the macrophage-activation phenotype., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

The hallmarks of age-related immune senescence are chronic inflammation, aberrant expansion of effector memory, and loss of naive T lymphocytes due in part to systemic activation of innate immune sensor NLRP3 inflammasome in myeloid lineage cells. The endogenous mechanisms that regulate inflammasome activation during aging are unknown. Here, we present evidence that growth hormone receptor (GH-R)-dependent downregulation of NLRP3 inflammasome in macrophages is linked to pro-longevity effects that maintain immune system homeostasis in aging. Deletion of GH-R prevented the macrophage-driven age-related activation of inflammasome in response to NLRP3 ligands and also increased the preservation of naive T cells, even in advanced age and with higher IFNγ secretion from effector cells. The mechanism of inflammasome inhibition is linked to autocrine somatotropic axis as ablation of IGF1R in macrophages lowered the NLRP3 inflammasome activation. Together, our findings show that functional somatotropic axis in macrophages controls inflammation, thus linking NLRP3-mediated innate immune signaling to health span and longevity., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Organogenesis of the thyroid gland requires the Pax8 protein. Absence or reduction of Pax8 results in congenital hypothyroidism in animal models and humans, respectively. This study aims at elucidating the regulatory mechanism leading to the expression of Pax8 in thyroid cells., Methods: The murine Pax8 gene promoter was functionally dissected by mutagenesis and transfection in the thyroid cell line FRTL-5. Nuclear factors important for thyroid-specific gene expression were identified by DNA-binding assays., Results: We show that Pax8 binds to and controls the expression of its own promoter. Furthermore, we identify a novel, thyroid-specific, DNA-binding activity (denominated nTTF [for novel Thyroid Transcription Factor]) that recognizes a specific region of the Pax8 promoter., Conclusions: The Pax8 promoter appears to be autoregulated, a feature that might be responsible for the haploinsufficiency displayed by this gene.

Cor triatriatum is a rare cardiac anomaly which can be congenital or acquired in origin. Congenital cor triatriatum is due to an alteration of the common pulmonary vein resorption and therefore the left atrium is divided into two chambers, a proximal one, in communication with the pulmonary veins, and a distal one, in communication with the mitral valve orifice. The diagnosis is usually made at birth, but in rare cases, when the communication between the two chambers is wide and the patient is asymptomatic, the lesions may be diagnosed incidentally during a routine echocardiographic examination. We report a 32-year-old man, admitted to our hospital with a diagnosis of aortic insufficiency, in whom echocardiography revealed the presence of cor triatriatum. The patient underwent aortic valve replacement and resection of the atrial membrane. Histology of the aortic valve revealed myxoid degeneration of the spongiosa.

The aim of this study was to analyse the risk factors in patients undergoing closed heart commissurotomy (CHC). From 1956 to 1978 a total of 630 patients with severe mitral stenosis underwent CHC at this Institute. The study was performed on a sample of 100 patients. Follow-up was performed using data taken from the Institute archives, questionnaires sent to the doctors in charge, telephone interviews or visits to outpatient clinics by the Institute's medical staff. The mortality rate 30 days after surgery was 2.9%. Re-CHC was necessary in 11 patients after a mean interval of 7.2 years. The overall probability of survival was 83%, 71%, 48% an 33% respectively at 10, 20, 30 and 40 years. Survival free from mitral re-operation at 10, 20, 30 and 40 years was 76%, 39%, 29% and 11% respectively. The probability of incidence for central and peripheral thromboembolism was 38%, 26%, 11% and 4% at 10, 20, 30 and 40 years. Mitral valve replacement surgery (MVR) was performed in a total of 64 patients. Operative mortality was 0.6% (1 patient). The mean duration of follow-up in patients undergoing post-CHC MVR was 10 years. The probability os survival in overall terms and free of cardiac decompensation was 79 and 53% respectively. From this study it is clear the CHC is a surgical procedure that offers excellent long-term results with a low incidence od thromboembolic events, very low costs and a good quality of life. CHC currently represents a valid alternative o mitral valve replacement in selected patients.

The authors report the results of more than five years experience of phlebectomies, according to Müller's method, performed both in general anesthesia during stripping operations and in local practice. The results confirmed the validity of this complementary surgical treatment for its radicality, execution simpleness and best respect for aesthetics.

Aim: The aim of the present study was to evaluate the quality of life after mitral valve replacement through the analysis of behavioural, psychological, functional, economic and working changes, as well as alterations in social and sexual life after surgery., Setting: The study was performed before and after surgery in a cardiological ward., Population: The population studied included 206 patients undergoing mitral valve replacement surgery. Results were compared with a control population of patients suffering from mitral valve disease and receiving medical therapy., Method: All patients were asked by medical staff to compile a series of five self-evaluation questionnaires: General Well-Being Schedule, Physical Symptoms Distress Index B, Social Participation, Sexual Satisfaction Unified Test and Work Performance and Satisfaction., Results: Our results showed a significant improvement in the perception of quality of life after mitral valve replacement. In particular, the state of general well-being improved significantly with a clear reduction in symptoms. This was accompanied by a reduction in sexual activity and no change in social life or working capacity. Data obtained in the group of patients operated showed a significant improvement in the perception of the quality of life and psycho-physical well-being compared to patients receiving medical treatment alone., Conclusions: From this study it can be seen that patients undergoing mitral valve replacement surgery experience a marked improvement in the quality of life compared to pre-operative conditions and to the group of patients receiving medical therapy for mitral valve diseases. The use of specific working and social rehabilitation programmes can certainly optimise the results also with regard to affective relations.

The aim of the present single blind study was the assessment of the effect of placebo on office (OBP) and 24-hour ambulatory (ABP) blood pressure in patients with mild and moderate essential hypertension (WHO stage I). Ten patients (6 males, 4 females, age 51 +/- 9 years) underwent both OBP and ABP measurements at the beginning and the end of a 2-week placebo treatment. The comparison of the results of the first (OBP 156/100 +/- 15/6 mmHg, day ABP 155/96 +/- 12/7 mmHg, night ABP 139/81 +/- 21/10 mmHg) and the second sets of measurements (OBP 152/98 +/- 22/7 mmHg, day ABP 147/90 +/- 15/7 mmHg, night ABP 134/79 +/- 18/7 mmHg) did not show a statistically significant drop in OBP and night ABP, while there was a statistically significant (p < 0.05) decrease in day ABP. Thus, the effect of placebo can influence day ABP measurements, even when OBP is not decreased by placebo administration. Possible explanations involve alerting reactions to the first ABP monitorings in selected patients with mild and even moderate hypertension.