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Mammalian adipose tissue is traditionally categorized into white and brown relating to their function and morphology: while white serves as an energy storage, brown adipose tissue acts as the heat generator maintaining the core body temperature. The most recently identified type of fat, beige adipocyte tissue, resembles brown fat by morphology and function but is developmentally more related to white. The synthesis of beige fat, so-called browning of white fat, has developed into a topical issue in diabetes and metabolism research. This is due to its favorable effect on whole-body energy metabolism and the fact that it can be recruited during adult life. Indeed, brown and beige adipose tissues have been demonstrated to play a role in glucose homeostasis, insulin sensitivity, and lipid metabolism—all factors related to pathogenesis of type 2 diabetes. Many agents capable of initiating browning have been identified so far and tested widely in humans and animal models including in vitro and in vivo experiments. Interestingly, several agents demonstrated to have browning activity are in fact secreted as adipokines from brown and beige fat tissue, suggesting a physiological relevance both in beige adipocyte recruitment processes and in maintenance of metabolic homeostasis. The newest findings on agents driving beige fat recruitment, their mechanisms, and implications on type 2 diabetes are discussed in this review.

Aging is widely regarded as an irreversible arrest of cellular growth and proliferation, often accompanied by systemic metabolic organ abnormalities, ultimately reducing quality of life and increasing mortality in the elderly. Multi-organ transcriptomic analyses suggest that adipose tissue is among the earliest organs to respond to aging, characterized by changes in fat content and redistribution of adipose tissue, decline in thermogenic adipose function, reduced proliferation and differentiation capacity of adipose progenitor and stem cells, accumulation of senescent cells, and immunosenescence. These alterations may act synergistically and play a role in abnormalities in metabolic organs including the cardiovascular, liver, skeletal muscle, and brain. Studies have demonstrated that exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities by inhibiting inflammation, reducing the accumulation of ectopic lipids, enhancing the browning of white adipose tissue and thermogenesis in brown adipose tissue, improving lipid metabolism, regulating the secretion of adipokines, and mitigating immunosenescence. This review summarizes the main characteristics of adipose tissue aging, the effects of adipose tissue aging on metabolic organ abnormalities, and the potential mechanisms by which exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities. It provides theoretical support for basic and clinical research on exercise-based prevention and treatment of aging-related diseases.

Long noncoding RNAs (lncRNAs) are an emerging class of regulators involved in a myriad of biological processes. Recent studies have revealed that many lncRNAs play pivotal roles in regulating adipocyte development. Due to the prevalence of obesity and the serious effects of adiposity on human health and society development, it is necessary to summarize functions and recent advances of lncRNAs in adipogenesis. In this review, we highlight functional lncRNAs contributed to the regulation of adipogenesis, discussing their potential use as therapeutic targets to combat human obesity.

Abstract Purpose Obesity is associated with alterations in appetite, gastrointestinal hormone levels and excessive fat mass. We previously published a double-blind, placebo-controlled, randomized, 16-week trial on effects of once-daily glucagon-like peptide-1 (GLP-1) analog, liraglutide on weight, satiation, and gastric functions in obese volunteers. The aim of this substudy is to compare to placebo the effects of liraglutide on appetite, taste preference, regional body fat stores, and anthropometric measurements. Methods Forty obese adults received standard instruction for weight management, monthly behavioral intervention utilizing motivational interviews, and 16-week treatment of once-daily liraglutide (escalated to 3 mg SQ daily). At baseline and 16 weeks, the following were measured: appetite and taste preferences rated every 30 min for 5 h after ingesting 300 mL Ensure®; maximal tolerated volume (MTV) with a nutrient drink test; fasting and postprandial bioactive GLP-1 (7–36) and peptide YY (PYY) levels; total and regional body fat with dual-energy X-ray absorptiometry, and waist and hip circumference. Results Thirty-five participants (17 liraglutide; 18 placebo) completed the trial. Compared to placebo group, liraglutide group had significant reductions in MTV; prospective food consumption score; desire to eat something sweet, salty, savory or fatty; and an increase in perceived fullness. Postprandial plasma levels of GLP-1 decreased and PYY levels increased with liraglutide relative to baseline. Significant reductions in total body, trunk, and upper and lower body fat without reduction in lean body mass were observed. Conclusion Liraglutide 3 mg SQ modulates appetite, taste preference, gut hormones, and regional body fat stores in adults with obesity without reduction in lean body mass.

Background Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has demonstrated cardiovascular and renal protection in patients with type 2 diabetes (T2D). We hypothesized that empaglifozin (EMPA) could modulate ectopic fat stores and myocardial energetics in high-fat-high-sucrose (HFHS) diet mice and in type 2 diabetics (T2D). Methods C57BL/6 HFHS mice ( n  = 24) and T2D subjects ( n  = 56) were randomly assigned to 12 weeks of treatment with EMPA (30 mg/kg in mice, 10 mg/day in humans) or with placebo. A 4.7 T or 3 T MRI with 1 H-MRS evaluation–myocardial fat (primary endpoint) and liver fat content (LFC)–were performed at baseline and at 12 weeks. In humans, standard cardiac MRI was coupled with myocardial energetics (PCr/ATP) measured with 31 P-MRS. Subcutaneous (SAT) abdominal, visceral (VAT), epicardial and pancreatic fat were also evaluated. The primary efficacy endpoint was the change in epicardial fat volume between EMPA and placebo from baseline to 12 weeks. Secondary endpoints were the differences in PCr/ATP ratio, myocardial, liver and pancreatic fat content, SAT and VAT between groups at 12 weeks. Results In mice fed HFHS, EMPA significantly improved glucose tolerance and increased blood ketone bodies (KB) and β-hydroxybutyrate levels ( p  < 0.05) compared to placebo. Mice fed HFHS had increased myocardial and liver fat content compared to standard diet mice. EMPA significantly attenuated liver fat content by 55%, ( p  < 0.001) but had no effect on myocardial fat. In the human study, all the 56 patients had normal LV function with mean LVEF = 63.4 ± 7.9%. Compared to placebo, T2D patients treated with EMPA significantly lost weight (− 2.6 kg [− 1.2; − 3.7]) and improved their HbA1c by 0.88 ± 0.74%. Hematocrit and EPO levels were significantly increased in the EMPA group compared to placebo ( p  < 0.0001, p  = 0.041). EMPA significantly increased glycosuria and plasma KB levels compared to placebo ( p  < 0.0001, p  = 0.012, respectively), and significantly reduced liver fat content (− 27 ± 23 vs. − 2 ± 24%, p  = 0.0005) and visceral fat (− 7.8% [− 15.3; − 5.6] vs. − 0.1% [− 1.1;6.5], p  = 0.043), but had no effect on myocardial or epicardial fat. At 12 weeks, no significant change was observed in the myocardial PCr/ATP ( p  = 0.57 between groups). Conclusions EMPA effectively reduced liver fat in mice and humans without changing epicardial, myocardial fat or myocardial energetics, rebutting the thrifty substrate hypothesis for cardiovascular protection of SGLT2 inhibitors. Trial registration NCT, NCT03118336. Registered 18 April 2017, https://clinicaltrials.gov/ct2/show/NCT03118336

Background:Nonalcoholic fatty liver disease is very frequent in type 2 diabetes, with increased risk of further development of liver fibrosis. Animal studies have shown that GLP-1 receptor agonists may reduce liver lipogenesis. However, data in humans are scarce.Objective:To study the effect of liraglutide 1.2 mg/d on liver fat content (LFC) in patients with uncontrolled type 2 diabetes and to evaluate the factors potentially associated with liraglutide-induced modification of LFC.Design, Setting, Participants:LFC was measured by proton magnetic resonance spectroscopy before and after 6 months of liraglutide treatment in 68 patients with uncontrolled type 2 diabetes mellitus.Intervention:Liraglutide 1.2 mg/d.Outcome measure:Change in LFC.Results:Treatment with liraglutide was associated with a significant decrease in body weight, HbA1C, and a marked relative reduction in LFC of 31% (P < 0.0001). No significant modification of LFC was observed in a parallel group of patients 6 months after intensification of the antidiabetic treatment with insulin. The reduction in LFC and body weight were highly correlated (r = 0.490; P < 0.0001). In multivariate analysis, the reduction in LFC was independently associated with baseline LFC (P < 0.0001), age (P = 0.010), and reduction in body weight (P < 0.0001), triglycerides (P = 0.019), and HbA1c (P = 0.034). In the patients who had no significant decrease in body weight, no significant reduction in LFC was observed.Conclusions:Six months of treatment with liraglutide 1.2 mg/d significantly reduced LFC in patients with inadequately controlled type 2 diabetes and this effect was mainly driven by body weight reduction. Further studies are needed to confirm that this reduction in LFC may significantly reduce fibrosis progression.We show in 68 patients with type 2 diabetes that 6 months of treatment with liraglutide significantly reduced liver fat content and that body weight reduction was the main driver of liver fat decrease.

Abstract Context Metabolic disturbances and a pro-inflammatory state associated with aging and obesity may be mitigated by physical activity or nutrition interventions. Objective The aim of this study is to assess whether physical fitness/exercise training (ET) alleviates inflammation in adipose tissue (AT), particularly in combination with omega-3 supplementation, and whether changes in AT induced by ET can contribute to an improvement of insulin sensitivity and metabolic health in the elderly. Design, Participants, Main Outcome Measures The effect of physical fitness was determined in cross-sectional comparison of physically active/physically fit (trained) and sedentary/less physically fit (untrained) older women (71 ± 4 years, n = 48); and in double-blind randomized intervention by 4 months of ET with or without omega-3 (Calanus oil) supplementation (n = 55). Physical fitness was evaluated by spiroergometry (maximum graded exercise test) and senior fitness tests. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Samples of subcutaneous AT were used to analyze mRNA gene expression, cytokine secretion, and immune cell populations. Results Trained women had lower mRNA levels of inflammation and oxidative stress markers, lower relative content of CD36+ macrophages, and higher relative content of γδT-cells in AT when compared with untrained women. Similar effects were recapitulated in response to a 4-month ET intervention. Content of CD36+ cells, γδT-cells, and mRNA expression of several inflammatory and oxidative stress markers correlated to insulin sensitivity and cardiorespiratory fitness. Conclusions In older women, physical fitness is associated with less inflammation in AT. This may contribute to beneficial metabolic outcomes achieved by ET. When combined with ET, omega-3 supplementation had no additional beneficial effects on AT inflammatory characteristics.

This study aimed to evaluate the safety and therapeutic potential of autologous human adipose-derived mesenchymal stem cells (haMSCs) in patients with osteoarthritis. Safety and efficacy of haMSCs were preclinically assessed and in BALB/c-nu nude mice. 18 patients were enrolled and divided into three dose groups: the low-dose, mid-dose and high-dose group (1 × 10 , 2 × 10 and 5 × 10 cells, respectively), provided three injections and followed up for 96 weeks. The preclinical study established the safety and efficacy of haMSCs. Intra-articular injections of haMSCs were safe and improved pain, function and cartilage volume of the knee joint, rendering them a promising novel treatment for knee osteoarthritis. The dosage of 5 × 10 haMSCs exhibited the highest improvement (ClinicalTrials.gov Identifier: NCT01809769).

Dietary intake of saturated fat is a likely contributor to nonalcoholic fatty liver disease (NAFLD) and insulin resistance, but the mechanisms that initiate these abnormalities in humans remain unclear. We examined the effects of a single oral saturated fat load on insulin sensitivity, hepatic glucose metabolism, and lipid metabolism in humans. Similarly, initiating mechanisms were examined after an equivalent challenge in mice. Fourteen lean, healthy individuals randomly received either palm oil (PO) or vehicle (VCL). Hepatic metabolism was analyzed using in vivo 13C/31P/1H and ex vivo 2H magnetic resonance spectroscopy before and during hyperinsulinemic-euglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses. PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-κB, and TNF-related weak inducer of apoptosis (TWEAK). Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD.REGISTRATION. ClinicalTrials.gov NCT01736202. Germany: Ministry of Innovation, Science, and Research North Rhine-Westfalia, German Federal Ministry of Health, Federal Ministry of Education and Research, German Center for Diabetes Research, German Research Foundation, and German Diabetes Association. Portugal: Portuguese Foundation for Science and Technology, FEDER - European Regional Development Fund, Portuguese Foundation for Science and Technology, and Rede Nacional de Ressonância Magnética Nuclear.

Long-chain omega 3 fatty acids, eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) exert potent anti-inflammatory properties in humans. This study characterized the effects of omega-3 ω-3 fatty acids supplements (ω-3 FA) on the inflammatory status in the placenta and adipose tissue of overweight/obese pregnant women. A randomized, double-masked controlled trial was conducted in overweight/obese pregnant women that were randomly assigned to receive DHA plus EPA (2 g/day) or the equivalent of a placebo twice a day from week 10-16 to term. Inflammatory pathways were characterized in: 1) adipose tissue and placenta of treated vs. untreated women; and 2) adipose and trophoblast cells cultured with long chain FAs. The sum of plasma DHA and EPA increased by 5.8 fold and ω-3 FA/ω-6 FA ratio was 1.5 in treated vs. untreated women (p< 0.005). Plasma CRP concentrations were reduced (p<0.001). The adipose tissue and placenta of treated women exhibited a significant decrease in TLR4 adipose and placental expression as well as IL6, IL8, and TNFα In vitro, EPA and DHA suppressed the activation of TLR4, IL6, IL8 induced by palmitate in culture of adipose and trophoblast cells. Supplementation of overweight/obese pregnant women with dietary ω-3 FAs for >25 weeks reduced inflammation in maternal adipose and the placental tissue. TLR4 appears as a central target of the anti-inflammatory effects at the cellular level. ClinicalTrials.gov NCT00957476.