Energy Metabolism In Adipose Tissue Research Articles

A Mixture of Lactobacillus HY7601 and KY1032 Regulates Energy Metabolism in Adipose Tissue and Improves Cholesterol Disposal in High-Fat-Diet-Fed Mice.

We aimed to characterize the anti-obesity and anti-atherosclerosis effects of Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032 using high-fat diet (HFD)-fed obese C57BL/6 mice. We divided the mice into control (CON), HFD, HFD with 108 CFU/kg/day probiotics (HFD + KL, HY7301:KY1032 = 1:1), and HFD with 109 CFU/kg/day probiotics (HFD + KH, HY7301:KY1032 = 1:1) groups and fed/treated them during 7 weeks. The body mass, brown adipose tissue (BAT), inguinal white adipose tissue (iWAT), and epididymal white adipose tissue (eWAT) masses and the total cholesterol and triglyceride concentrations were remarkably lower in probiotic-treated groups than in the HFD group in a dose-dependent manner. In addition, the expression of uncoupling protein 1 in the BAT, iWAT, and eWAT was significantly higher in probiotic-treated HFD mice than in the HFD mice, as demonstrated by immunofluorescence staining and Western blotting. We also measured the expression of cholesterol transport genes in the liver and jejunum and found that the expression of those encoding liver-X-receptor α, ATP-binding cassette transporters G5 and G8, and cholesterol 7α-hydroxylase were significantly higher in the HFD + KH mice than in the HFD mice. Thus, a Lactobacillus HY7601 and KY1032 mixture with 109 CFU/kg/day concentration can assist with body weight regulation through the management of lipid metabolism and thermogenesis.

Anti-Obesity Effect of Jeju Roasted Citrus Peel Extract in High-Fat Diet-Induced Obese Mice and 3T3-L1 Adipocytes Via Lipid Metabolism Regulation.

Lipid accumulation in adipocytes occurs through multifactorial effects such as overnutrition due to unbalanced eating habits, reduced physical activity, and genetic factors. In addition, obesity can be intensified by the dis-regulation of various metabolic systems such as differentiation, lipogenesis, lipolysis, and energy metabolism of adipocytes. In this study, the Jeju roasted peel extract from Citrus unshiu S.Markov. (JRC), which is discarded as opposed to the pulp of C. unshiu S.Markov., is commonly consumed to ameliorate obesity. To investigate the anti-obesity effect of JRC, these studies were conducted on differentiated 3T3-L1 cells and in high-fat diet-induced mice, and related methods were used to confirm whether it decreased lipid accumulation in adipocytes. The mechanism of inhibiting obesity by JRC was confirmed through mRNA expression studies. JRC suppressed lipid accumulation in adipocytes and adipose tissue, and significantly improved enzymes such as alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase and serum lipid profiles. In addition, it effectively modulated the expression of genes related to lipid and energy metabolism in adipose tissue. As a result, these findings suggest that JRC could be a therapeutic regulator of body fat accumulation by significantly alleviating the dis-regulation of intracellular lipid metabolism in adipocytes and by enhancement of energy metabolism (Approval No. CNU IACUC-YB-2023-98).

Oral administration of kynurenic acid delays the onset of type 2 diabetes in Goto-Kakizaki rats

Kynurenic acid (KYNA) is an endogenous catabolite of tryptophan that has been found to demonstrate neuroprotective properties in psychiatric disorders. Recently, accumulating data have suggested that KYNA may also play a significant role in various metabolic diseases by stimulating energy metabolism in adipose tissue and muscle. However, whether KYNA can serves as an anti-diabetes agent has yet to be studied. In this study, we investigated the potential anti-diabetic effects of administering KYNA orally through drinking water in pre-diabetic Goto-Kakizaki rats and examined how this treatment may influence energy metabolism regulation within the liver. We found that hyperglycemic Goto-Kakizaki rats showed lower plasmatic KYNA levels compared to normal rats. Oral administration of KYNA significantly delayed the onset of diabetes in Goto-Kakizaki rats compared to untreated animals. Moreover, we found that KYNA treatment significantly increased respiration exchange ratio and promoted the energy expenditure by stimulating the expression of uncoupling protein (UCP). We confirmed that KYNA stimulated the UCP expression in HepG2 cells and mouse hepatocytes at mRNA and protein levels. Our study reveals that KYNA could potentially act as an anti-diabetic agent and KYNA-induced UCP upregulation is closely associated with the regulation of energy metabolism. These results provide further evidence for the therapeutic potential of KYNA in diabetes.

Visceral Adipose Tissue Bioenergetics Varies According to Individuals' Obesity Class.

Obesity is associated with complex adipose tissue energy metabolism remodeling. Whether AT metabolic reprogramming differs according to body mass index (BMI) and across different obesity classes is unknown. This study’s purpose was to evaluate and compare bioenergetics and energy substrate preference of visceral adipose tissue (VAT) pertaining to individuals with obesity class 2 and class 3. VAT obtained from patients with obesity (n = 15) class 2 (n = 7; BMI 37.53 ± 0.58 kg/m2) or class 3 (n = 8; BMI 47.79 ± 1.52 kg/m2) was used to assess oxygen consumption rate (OCR) bioenergetics and mitochondrial substrate preferences. VAT of patients with obesity class 3 presented significantly higher non-mitochondrial oxygen consumption (p < 0.05). In VAT of patients with obesity class 2, inhibition of pyruvate and glutamine metabolism significantly decreased maximal respiration and spare respiratory capacity (p < 0.05), while pyruvate and fatty acid metabolism inhibition, which renders glutamine the only available substrate, increased the proton leak with a protective role against oxidative stress (p < 0.05). In conclusion, VAT bioenergetics of patients with obesity class 2 depicts a greater dependence on glucose/pyruvate and glutamine metabolism, suggesting that patients within this BMI range are more likely to be responsive to interventions based on energetic substrate modulation for obesity treatment.

PMON182 PACAP Receptor Expression in Sympathetic Ganglia of the Autonomic Nervous System

Abstract In obesity, energy intake exceeds energy expenditure and concomitantly increases risk of chronic diseases, including metabolic diseases such as diabetes. Therapeutics to correct dysregulations in energy balance are needed and one notable neuropeptide being studied is pituitary adenylate cyclase-activating polypeptide (PACAP), an overarching regulator of the stress response1,2. In the context of metabolism, PACAP has been shown to regulate adaptive thermogenesis, an energy burning process regulated by the sympathetic nervous system (SNS) in response to cold stress and overfeeding. While research suggests PACAP acts centrally at the level of the hypothalamus to regulate energy balance3-5, PACAP is also known to be expressed in the SNS. In preganglionic neurons innervating the adrenal medulla6, PACAP is co-localized with acetylcholine and regulates catecholamine synthesis and release. Recent neuronal tracing studies have shown that postganglionic fibres of the stellate ganglia innervate intrascapular brown adipose tissue (BAT), the main thermogenic tissue in mammals7. However, PACAP's role within the sympathetic nerves innervating and regulating energy metabolism in adipose tissues is not known. As such, our group is interested in characterizing PACAP and PACAP receptor expression in sympathetic nerves innervating and regulating energy metabolism in BAT (via the stellate ganglia) in response to metabolic stressors, such as cold stress. We hypothesize that PACAP is released from preganglionic nerves which binds PACAP receptors (PAC1, VPAC1, VPAC2) expressed in postganglionic nerves of the stellate ganglia. Here we report, for the first time, PAC1 and VPAC1 expression in the stellate ganglia with sex-specific differential gene expression based on housing temperature. Analysis of PAC1 splice variant expression identified at least two variants in tissues of the SNS (adrenal gland, superior cervical ganglia and the stellate ganglia). These results will support future functional studies characterizing PACAP regulation of catecholamine production in peripheral ganglia which will contribute to assessing G-protein coupled receptors (GPCRs) as potential therapeutic targets for obesity and metabolic disease.

Prolyl Isomerase Pin1 Impacts on Metabolism in Muscle and Adipocytes

Prolyl isomerase Pin1 is associated with various substrates and controls their functions through the isomerization of proline. Interestingly, a high fat diet increases Pin1 levels in adipose tissues. Accordingly, we investigated how Pin1 regulates energy metabolism in adipose tissues. Currently, adipocytes are divided into three types with distinct features. White adipocytes (WATs) store energy as triglycerides under fed conditions and release non-esterified fatty acids and glycerol through lipolysis while fasting. Brown and beige adipocytes, which exist in subcutaneous fat (scWAT), promote energy consumption through thermogenesis. We found that Pin1 impacts both thermogenesis and lipolysis upon interaction with distinct substrates. When mice were exposed to cold stress, both brown adipose tissues (BAT) and scWAT from adipocyte-specific Pin1 knockout (KO) mice showed higher expression levels of thermogenic genes in comparison to those from wild-type mice. Furthermore, we observed that Pin1 binds to the PRDM16 transcriptional cofactor, a major contributor to thermogenic programs, and promotes its degradation. Therefore, Pin1 suppresses thermogenesis. Meanwhile, in white adipocytes, Pin1 is involved in lipolysis. Pin1 deficiency enhanced lipolysis activity in epididymal WAT (epiWAT), but not in scWAT and BAT. In epiWAT, Pin1 interacts with adipose triglyceride lipase (ATGL) which is a rate-limiting enzyme for lipolysis, and downregulates ATGL levels. Finally, adipocyte-specific Pin1 KO mice have less body weight and better glucose metabolism under high fat diet conditions. These observations indicate that Pin1 is involved in the function of adipocytes through its association with PRDM16 and ATGL. Pin1 inhibitors could have therapeutic applications in the treatment of obesity.

First person – Jiří Funda

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models &amp; Mechanisms, helping early-career researchers promote themselves alongside their papers. Jiří Funda is first author on ‘ Adipose tissue-specific ablation of PGC-1β impairs thermogenesis in brown fat’, published in DMM. Jiří is a PhD student in the lab of Martin Rossmeisl at The Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic, investigating adipose tissue energy metabolism and its modulation by pathological conditions such as obesity.

Cold Exposure Induces Depot-Specific Alterations in Fatty Acid Composition and Transcriptional Profile in Adipose Tissues of Pigs.

Cold exposure promotes fat oxidation and modulates the energy metabolism in adipose tissue through multiple mechanisms. However, it is still unclear about heat-generating capacity and lipid mobilization of different fat depots without functional mitochondrial uncoupling protein 1 (UCP1). In this study, we kept finishing pigs (lack a functional UCP1 gene) under cold (5-7°C) or room temperature (22-25°C) and determined the effects of overnight cold exposure on fatty acid composition and transcriptional profiles of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). And the plasma metabolomes of porcine was also studied by LC-MS-based untargeted metabolomics. We found that the saturated fatty acids (SFAs) content was decreased in SAT upon cold exposure. While in VAT, the relative content of lauric acid (C12:0), myristic acid (C14:0) and lignoceric acid (C24:0) were decreased without affecting total SFA content. RNA-seq results showed SAT possess active organic acid metabolism and energy mobilization upon cold exposure. Compared with SAT, cold-induced transcriptional changes were far less broad in VAT, and the differentially expressed genes (DEGs) were mainly enriched in fat cell differentiation and cell proliferation. Moreover, we found that the contents of organic acids like creatine, acamprosate, DL-3-phenyllactic acid and taurine were increased in plasma upon overnight cold treatment, suggesting that cold exposure induced lipid and fatty acid metabolism in white adipose tissue (WAT) might be regulated by functions of organic acids. These results provide new insights into the effects of short-term cold exposure on lipid metabolism in adipose tissues without functional UCP1.

Rutin promotes white adipose tissue "browning" and brown adipose tissue activation partially through the calmodulin-dependent protein kinase kinase β/AMP-activated protein kinase pathway.

Promoting white adipose tissue (WAT) "browning" and brown adipose tissue (BAT) activation could contribute to increasing energy expenditure. We explored the mechanisms by which the natural compound rutin induced adipose tissue differentiation and ameliorated obesity in vivo and in vitro. 3T3-L1 preadipocytes were cultured in adipogenic differentiation media with/out rutin. Male C57BL/6 mice (n = 6) were fed a high-fat diet (HFD) for 12 weeks with/out rutin. In HFD-fed mice, rutin treatment significantly inhibited weight gain, improved the metabolic profile of plasma samples, decreased the weights of epididymal WAT (eWAT), inguina WAT (iWAT), and liver, and adipocyte size. Furthermore, rutin also increased the expression of uncoupling protein 1 (Ucp-1) and other thermogenic markers in the WAT and BAT. In 3T3-L1 cells, rutin effectively reduced the formation of lipid droplets, stimulated the expression of thermogenic markers, and reduced the expression of adipogenic genes. Additionally, rutin markedly upregulated the AMP-activated protein kinase (AMPK) pathway, and these effects were diminished by treatment with the AMPK inhibitor compound C (CC). Pretreatment with the calmodulin-dependent protein kinase kinase β (CaMKKβ) inhibitor STO-609 blocked the induction of thermogenic markers in 3T3-L1 cells by rutin. Our results indicated that rutin increased energy consumption, induced WAT "browning" and BAT activation, and thus was a promising target for the development of new therapeutic approaches to improve adipose tissue energy metabolism.

HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue

ObjectiveInsulin regulates mitochondrial function, thereby propagating an efficient metabolism. Conversely, diabetes and insulin resistance are linked to mitochondrial dysfunction with a decreased expression of the mitochondrial chaperone HSP60. The aim of this investigation was to determine the effect of a reduced HSP60 expression on the development of obesity and insulin resistance. MethodsControl and heterozygous whole-body HSP60 knockout (Hsp60+/−) mice were fed a high-fat diet (HFD, 60% calories from fat) for 16 weeks and subjected to extensive metabolic phenotyping. To understand the effect of HSP60 on white adipose tissue, microarray analysis of gonadal WAT was performed, ex vivo experiments were performed, and a lentiviral knockdown of HSP60 in 3T3-L1 cells was conducted to gain detailed insights into the effect of reduced HSP60 levels on adipocyte homeostasis. ResultsMale Hsp60+/− mice exhibited lower body weight with lower fat mass. These mice exhibited improved insulin sensitivity compared to control, as assessed by Matsuda Index and HOMA-IR. Accordingly, insulin levels were significantly reduced in Hsp60+/− mice in a glucose tolerance test. However, Hsp60+/− mice exhibited an altered adipose tissue metabolism with elevated insulin-independent glucose uptake, adipocyte hyperplasia in the presence of mitochondrial dysfunction, altered autophagy, and local insulin resistance. ConclusionsWe discovered that the reduction of HSP60 in mice predominantly affects adipose tissue homeostasis, leading to beneficial alterations in body weight, body composition, and adipocyte morphology, albeit exhibiting local insulin resistance.

The Role of Vitamin D in Adipose Tissue Biology: Adipocyte Differentiation, Energy Metabolism, and Inflammation.

Adipose tissue is composed of diverse cell types and plays a major role in energy homeostasis and inflammation at the local and systemic levels. Adipose tissue serves as the main site for vitamin D storage and is among the most important extraskeletal targets of vitamin D which can modulate multiple aspects of adipose tissue biology. Vitamin D may exert inhibitory or stimulatory effects on adipocyte differentiation depending on cell type, stage of differentiation, and the treatment time point. Moreover, vitamin D controls energy metabolism in adipose tissue by affecting fatty acid oxidation, expression of uncoupling proteins, insulin resistance, and adipokine production. Adipose tissue inflammation can have a significant impact on the metabolic disorders often associated with obesity, and vitamin D can modulate the inflammatory response of immune cells and adipocytes within the adipose tissue. This review discusses the role of adipose tissue in vitamin D metabolism, as well as the regulatory role of vitamin D in adipocyte differentiation, adipose tissue energy metabolism, and inflammation, thereby providing insights into the importance of vitamin D in adipose tissue biology.

Forkhead box P1 (Foxp1) in osteoblasts regulates bone mass accrual and adipose tissue energy metabolism.

Adiponectin (AdipoQ), a hormone abundantly secreted by adipose tissues, has multiple beneficial functions, including insulin sensitization as well as lipid and glucose metabolism. It has been reported that bone controls energy metabolism through an endocrine-based mechanism. In this study, we observed that bone also acts as an important endocrine source for AdipoQ, and its capacity in osteoblasts is controlled by the forkhead box P1 (FOXP1) transcriptional factor. Deletion of the Foxp1 gene in osteoblasts led to augmentation of AdipoQ levels accompanied by fueled energy expenditure in adipose tissues. In contrast, overexpression of Foxp1 in bones impaired AdipoQ secretion and restrained energy consumption. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis revealed that AdipoQ expression, which increases as a function of bone age, is directly controlled by FOXP1. Our results indicate that bones, especially aged bones, provide an important source of a set of endocrine factors, including AdipoQ, that control body metabolism. © 2021 American Society for Bone and Mineral Research (ASBMR).

1822-P: Regulation of Trafficking of Lipids from Liver to Fat by ApoA4 in a Mouse Model of Nonalcoholic Steatohepatitis

Lipogenesis and lipolysis largely determining adipose tissues and liver lipid content, and the imbalance between them contributes to fatty liver disease and metabolic syndromes. Lipogenesis and lipolysis are regulated by nutritional signals and metabolic hormones such as insulin through multiple mechanisms. Apolipoprotein A-IV (ApoA4), secreted largely by intestine, is existed as the composition of HDL and as the free form mostly in blood. ApoA4 plays the important roles in anti-atherosclerosis and lowering blood glucose. After we found its suppressing hepatic gluconeogenesis via NR1D1/NR4A1, and promoting glucose uptake in adipose tissues through PI3K-Akt-GLUT4, we have studied the action of ApoA4 on lipid metabolism with ApoA4 knock-out mice (A4KO). We found that ApoA4 deficiency resulted in worse fatty liver in diet induced obesity (DIO) mice. ApoA4 deficiency lowered the expression of hepatic ATGL, the rate-limiting enzyme for lipolysis, but enhanced the expression of key lipogenic enzymes such as ACC and SCD1. However, the expression of ATGL was increased and the expression of ACC, SCD1, FAS as well as their transcriptional activator SREBP1 were decreased from both BAT and WAT in A4KO mice. Furthermore, ApoA4 deletion also resulted in the inhibited expression of key proteins in thermogenesis pathway SIRT1, PGC1 and UCP1. Moreover, either overexpression of ApoA4 by delivery of AAV-ApoA4 or one time injection of ApoA4 protein resulted in reversed expression of key enzymes for lipogenesis and lipolysis both in liver and adipose tissues from A4KO DIO mice. These data suggest that ApoA4 may promote lipolysis in liver, but inhibited lipolysis and enhance lipogenesis and energy metabolism in adipose tissues, implying ApoA4’s action of regulating the trafficking of lipids from liver to fat and then turn fat into energy for burning. Disclosure X. Li: None. X. Liu: None. C. Cheng: None. J. Zhou: None. J. Fan: None. S. Li: None. Funding National Natural Science Foundation of China (81770798, 81700691)

Expansion and Impaired Mitochondrial Efficiency of Deep Subcutaneous Adipose Tissue in Recent-Onset Type 2 Diabetes.

Context/ObjectiveImpaired adipose tissue (AT) function might induce recent-onset type 2 diabetes (T2D). Understanding AT energy metabolism could yield novel targets for the treatment of T2D.Design/PatientsMale patients with recently-diagnosed T2D and healthy male controls (CON) of similar abdominal subcutaneous AT (SAT)-thickness, fat mass, and age (n = 14 each), underwent hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose and indirect calorimetry. We assessed mitochondrial efficiency (coupling: state 3/4o; proton leak: state 4o/u) via high-resolution respirometry in superficial (SSAT) and deep (DSAT) SAT-biopsies, hepatocellular lipids (HCL) and fat mass by proton-magnetic-resonance-spectroscopy and -imaging.ResultsT2D patients (known diabetes duration: 2.5 [0.1; 5.0] years) had 43%, 44%, and 63% lower muscle insulin sensitivity (IS), metabolic flexibility (P < 0.01) and AT IS (P < 0.05), 73% and 31% higher HCL (P < 0.05), and DSAT-thickness (P < 0.001), but similar hepatic IS compared with CON. Mitochondrial efficiency was ~22% lower in SSAT and DSAT of T2D patients (P < 0.001) and ~8% lower in SSAT vs DSAT (P < 0.05). In both fat depots, mitochondrial coupling correlated positively with muscle IS and metabolic flexibility (r ≥ 0.40; P < 0.05), proton leak correlated positively (r ≥ 0.51; P < 0.01) and oxidative capacity negatively (r ≤ −0.47; P < 0.05) with fasting free fatty acids (FFA). Metabolic flexibility correlated positively with SAT-oxidative capacity (r ≥ 0.48; P < 0.05) and negatively with DSAT-thickness (r = −0.48; P < 0.05). DSAT-thickness correlated negatively with mitochondrial coupling in both depots (r ≤ −0.50; P < 0.01) and muscle IS (r = −0.59; P < 0.01), positively with FFA during clamp (r = 0.63; P < 0.001) and HCL (r = 0.49; P < 0.01).ConclusionsImpaired mitochondrial function, insulin resistance, and DSAT expansion are AT abnormalities in recent-onset T2D that might promote whole-body insulin resistance and increased substrate flux to the liver.

Hepatic exosome-derived miR-130a-3p attenuates glucose intolerance via suppressing PHLPP2 gene in adipocyte

ObjectiveGlucose and lipid metabolism disorders are a major risk factor for type II diabetes and cardiovascular diseases. Evidence has indicated that the interplay between the liver and adipose tissue is crucial in maintaining energy homeostasis. Recently, the interaction between two distant endocrine organs mainly focuses on the regulation of hormones and receptors. However, as a novel carrier in the inter-tissue communication, exosomes plays a role in liver-fat crosstalk, but its effects on glucose and lipid metabolisms are still unclear. In this study, we sought to investigate the effects of hepatic exosome-derived miR-130a-3p in the regulation of glucose/lipid metabolism in adipose tissues. MeasureIn vivo, we constructed generalized miR-130a-3p knockout (130KO) and overexpressed (130OE) mice. Wild type (WT), 130KO and 130OE mice (n = 10) were assigned to a randomized controlled trial and were fed diets with either 10% (standard diet, SD) or 60% (high-fat diet, HFD) of total calories from fat (lard). Next, hepatic exosomes were extracted from WT-SD, 130KO-SD and 130OE-SD mice (WT-EXO, KO-EXO, OE-EXO), and 130KO mice were injected with 100 mg hepatic exosomes of different sources via tail-vein (once every 48 h) for 28 days, fed with HFD. In vitro, 3T3-L1 cells were treated with miR-130a-3p mimics, inhibitor and hepatic exosomes. Growth performance and glucose and lipid metabolic profiles were examined. ResultsAfter feeding with HFD, the weights of 130KO mice were markedly higher than WT mice. Over-expression of miR-130a-3p in 130OE mice and intravenous injection of 130OE-EXO in 130KO mice contributed to a positive correlation with the recovery of insulin resistance. In addition, miR-130a-3p mimics and 130OE-EXO treatment of 3T3-L1 cells exhibited decreasing generations of lipid droplets and increasing glucose uptake. Conversely, inhibition of miR-130a-3p in vitro and in vivo resulted in opposite phenotype changes. Furthermore, PHLPP2 was identified as a direct target of miR-130a-3p, and the hepatic exosome-derived miR-130a-3p could improve glucose intolerance via suppressing PHLPP2 to activate AKT-AS160–GLUT4 signaling pathway in adipocytes. ConclusionsWe demonstrated that hepatic exosome-derived miR-130a regulated energy metabolism in adipose tissues, and elucidated a new molecular mechanism that hepatic exosome-derived miR-130a-3p is a crucial participant in organismic energy homeostasis through mediating crosstalk between the liver and adipose tissues.

P.21Genetic analysis of first-degree relatives with inclusion body myositis

Inclusion body myositis (IBM) is a sporadic clinicopathologically defined myopathy characterised by finger flexor and quadriceps weakness, along with the histological triad of endomysial autoaggressive inflammation, rimmed vacuoles and protein aggregates. Rare familial occurrences of IBM have however been reported. We have identified 3 such families. Families 1 and 2 consisted of pairs of affected siblings, while family 3 consisted of a mother and her two children. The onset of symptoms was between 55 and 73 years. Patients displayed finger flexion greater than shoulder abduction and/or quadriceps greater than iliopsoas weakness. One individual in family 3 developed amyotrophic lateral sclerosis (ALS) 5 years after the diagnosis of IBM. An autoaggressive endomysial inflammatory infiltrate was present in all patients, while congophilic inclusions and rimmed vacuoles were observed in 6 and 5 patients, respectively. Anti-cytosolic 5′-nucleotidase 1A (cN1A) antibodies were present in the only 2 patients tested. Whole genome sequencing was performed in all patients and failed to identify causative variants in well-characterised Mendelian myopathy genes, including myopathies with rimmed vacuoles. The two siblings of family 1 both carried a heterozygous frameshift variant in TANK binding kinase 1 (TBK1). In the other 2 families, no candidate variant has so far been identified. Loss-of-function variants in TBK1 have recently been reported to cause ALS. TBK1 is a ubiquitously-expressed protein kinase known to regulate autophagy, mitophagy, neuroinflammation and adipose tissue energy metabolism. Several of these pathways have been hypothesised to play a role in the development of IBM. Further research is therefore warranted to explore the role of TBK1 in the pathogenesis of both familial and sporadic IBM.

β-Cryptoxanthin Induces UCP-1 Expression via a RAR Pathway in Adipose Tissue

While β-cryptoxanthin is hypothesized to have a preventive effect on lifestyle-related diseases, its underlying mechanisms are unknown. We investigated the effect of β-cryptoxanthin on energy metabolism in adipose tissues and its underlying mechanism. C57BL/6J mice were fed a high-fat diet (60% kcal fat) containing 0 or 0.05% β-cryptoxanthin for 12 weeks. β-cryptoxanthin treatment was found to reduce body fat gain and plasma glucose level, while increasing energy expenditure. The expression of uncoupling protein (UCP) 1 was elevated in adipose tissues in the treatment group. Furthermore, the in vivo assays showed that the Ucp1 mRNA expression was higher in the β-cryptoxanthin treatment group, an effect that disappeared upon cotreatment with a retinoic acid receptor (RAR) antagonist. In conclusion, we report that β-cryptoxanthin reduces body fat and body weight gain and that β-cryptoxanthin increases the expression of UCP1 via the RAR pathway.

Aging-associated impairment in metabolic compensation by subcutaneous adipose tissue promotes diet-induced fatty liver disease in mice.

Background and aimsNonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, and its progression is associated with aging-associated impairment in metabolic homeostasis. Recently, energy metabolism in adipose tissue has been the subject of renewed interest, because significant energy expenditure can be induced in cells derived from white adipose tissue progenitors, in addition to brown adipose tissue (BAT). Here we evaluated whether aging-associated change in various adipose tissue depots affects the progression of NAFLD.MethodsSix-week-old male C57BL/6NCrSlc mice were fed control chow (C) or high-fat diet (60% fat; HF) for 12 or 24 weeks (12w/C, 12w/HF, 24w/C and 24w/HF groups, respectively) or switched from C to HF diet at 18 weeks of age (24w/C/HF group) and fed for a further 24 weeks. Some 24w/HF mice received a subcutaneous transplantation of adipose progenitors (106 cells/mouse) from young donor mice. Basal energy expenditure, glucose tolerance, and liver and adipose tissue histology were then evaluated. In addition, features of senescence and the capacity of adipose progenitors to “brown” were compared in mice of various ages.Results12w/HF mice demonstrated compensation in the forms of hypertrophy of interscapular classical BAT and the appearance of subcutaneous beige adipocytes, consistent with improved metabolic homeostasis. In contrast, 24w/HF and 24w/C/HF mice developed obesity, glucose intolerance, and severe NAFLD, with accelerated senescence and loss of adipose progenitors in subcutaneous fat tissues. Recruitment of adipose progenitors ameliorated these findings in 24w/HF mice.ConclusionImpaired metabolic compensation in adipose tissue resulted in the progression of NAFLD, which was associated with aging-related deterioration in adipose progenitors. A new approach targeting adipose tissue progenitors might represent a potential strategy for the prevention of NAFLD.

Regulation of Adaptive Thermogenesis and Browning by Prebiotics and Postbiotics.

Prebiotics are non-digestible food components able to modify host microbiota toward a healthy profile, concomitantly conferring general beneficial health effects. Numerous research works have provided wide evidence regarding the effects of prebiotics on the protection against different detrimental phenotypes related to cancer, immunity, and features of the metabolic syndrome, among others. Nonetheless, one topic less studied so far, but relevant, relates to the connection between prebiotics and energy metabolism regulation (and the prevention or treatment of obesity), especially by means of their impact on adaptive (non-shivering) thermogenesis in brown adipose tissue (BAT) and in the browning of white adipose tissue (WAT). In the present review, a key link between prebiotics and the regulation of adaptive thermogenesis and lipid metabolism (in both BAT and WAT) is proposed, thus connecting prebiotic consumption, microbiota selection (especially gut microbiota), production of microbiota metabolites, and the regulation of energy metabolism in adipose tissue, particularly regarding the effects on browning promotion, or on BAT recruitment. In this sense, various types of prebiotics, from complex carbohydrates to phenolic compounds, have been studied regarding their microbiota-modulating role and their effects on crucial tissues for energy metabolism, including adipose tissue. Other studies have analyzed the effects of the main metabolites produced by selected microbiota on the improvement of metabolism, such as short chain fatty acids and secondary bile acids. Here, we focus on state-of-the-art evidence to demonstrate that different prebiotics can have an impact on energy metabolism and the prevention or treatment of obesity (and its associated disorders) by inducing or regulating adaptive thermogenic capacity in WAT and/or BAT, through modulation of microbiota and their derived metabolites.

Microdialysis-Assessed Adipose Tissue Metabolism, Circulating Cytokines and Outcome in Critical Illness.

Microdialysis (MD) can provide continuous information about tissue composition. To assess in critically ill patients adipose tissue metabolic patterns, the relationships between metabolic patterns and blood cytokine concentration associations of adipose tissue energy metabolism and clinical outcome we studied 203 mechanically ventilated general intensive care unit (ICU) patients. Upon ICU admission an MD catheter was inserted into the subcutaneous adipose tissue of the upper thigh to measure lactate (L), glucose, pyruvate (P), and glycerol. Serum concentrations of IL-10, IL-6, IL-8, and TNF-α were determined within 48 h from ICU admission. Mitochondrial dysfunction was defined as L/P ratio >30 and pyruvate ≥70 μmol/L, ischemia as L/P ratio >30 and pyruvate <70 μmol/L and no ischemia/no mitochondrial dysfunction (i.e., aerobic metabolism) was as L/P ratio ≤30. Metabolism was aerobic in 74% of patients. In 13% of patients there was biochemical evidence of ischemia and in 13% of patients of mitochondrial dysfunction. Mitochondrial dysfunction was associated with poor outcome. In conclusion, MD showed that about two thirds of critically ill patients have normal aerobic adipose tissue metabolism. Mitochondrial dysfunction was not common but was associated with poor outcome. Identifying subgroups of critically ill patients is crucial as different treatment strategies may improve survival.