Visceral Adipocytes Research Articles

Short-Term Zinc Supplementation Stimulates Visceral Adipose Catabolism and Inflammation in Mice.

Zinc (Zn), a fundamental trace element in human biology, exhibits pivotal roles in sustaining vital physiological processes and regulating metabolic homeostasis. Insufficient zinc intake has been linked to deleterious consequences on growth, reproductive functions, metabolic activities, and immune responses in both humans and animals. Oral zinc supplementation is usually performed to meet zinc requirement. Previous studies have shown that long-term supplementation of zinc in mice impaired AKT signaling and induced adipocyte hypertrophy in visceral adipose tissue. The presented study was conducted to investigate the role and mechanism of short-term zinc supplementation on lipids metabolism. Zinc sulfate was supplemented in the drinking water of C57/BL6J male mice at 30 ppm or 90 ppm for one week. Water consumption, food intake, and body weight were analyzed, adipose tissue and serum profile of metabolites were investigated, and the key genes related to lipid metabolism were analyzed. Short-term zinc supplementation decreased visceral adipose tissue weight and adipocyte size compared to the control group, but no difference was observed in food intake, water consumption, and body weight between the two groups. Further studies revealed that short-term zinc supplementation significantly increased the serum insulin level while decreasing the serum NEFA content. In addition, zinc supplementation increased the expression of Atgl and Hsl in the visceral adipose tissue compared with the control mice. Furthermore, the phosphorylation level of HSL and protein level of PPARg in the epididymal adipose tissue increased by zinc supplementation compared with the control mice. In comparison, the protein level of FASN was down-regulated by short-term zinc supplementation in the epididymal adipose tissue, although the expression of lipogenic genes was not changed. The expression of F4/80 and Tnfa were increased in zinc-supplemented adipose tissue as compared with the control group. Our findings suggest that short-term zinc supplementation might reduce fat deposition by enhancing lipolysis in mice. Future studies could focus on the effect of intermittent zinc supplementation on fat reduction in both animal models and humans.

Differential mitochondrial adaptation and FNDC5 production in brown and white adipose tissue in response to cold and obesity.

Fibronectin type III domain-containing protein 5 (FNDC5) modulates adipocyte metabolism by increasing white and brown adipose tissue (WAT and BAT) browning and activity, respectively. We investigated whether FNDC5 can regulate visceral WAT and BAT adaptive thermogenesis by improving mitochondrial homeostasis in response to cold and obesity. Adipose tissue expression of FNDC5 and factors involved in mitochondrial homeostasis were determined in patients with normal weight and obesity (n = 159) and in rats with diet-induced obesity after 1 week of cold exposure (n = 61). The effect of different FNDC5 concentrations on mitochondrial biogenesis, dynamics, and mitophagy was evaluated in vitro in human adipocytes. In human visceral adipocytes, FNDC5/irisin triggered mitochondrial biogenesis (TFAM) and fusion (MFN1, MFN2, and OPA1) while inhibiting peripheral fission (DNM1L and FIS1) and mitophagy (PINK1 and PRKN). Circulating and visceral WAT expression of FNDC5 wasdecreased in patients and experimental animals with obesity, whereas its receptor, integrin αV, was upregulated. Obesity increased mitochondrial fusion while decreasing mitophagy in visceral WAT from patients and rats. By contrast, in rat BAT, an upregulation of Fndc5 and genes involved in mitochondrial biogenesis and fission was observed. Cold exposure promoted mitochondrial biogenesis and healthy peripheral fission while repressing Fndc5 expression and mitophagy in BAT from rats. Depot differences in FNDC5 production and mitochondrial adaptations in response to obesity and cold might indicate a self-regulatory mechanism to control thermogenesis in response to energy needs.

Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review.

Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.

Metabolic effects of physical exercise on zebrafish (Danio rerio) fed a high-fat diet.

The present study aimed to establish zebrafish as an experimental model for investigations into obesity and physical exercise, as well as to assess the effects of these factors on metabolism. The experiment spanned twelve weeks, comprising a feeding trial during which the last four weeks incorporated a physical exercise protocol. This protocol involved placing fifteen animals in a five-liter aquarium, where they were subjected to swimming at an approximate speed of 0.08m/s for 30min daily. Throughout the experiment, histological analyses of visceral, subcutaneous, and hepatic adipose tissues were conducted, along with biochemical analyses of total cholesterol and its fractions, triglycerides, glucose, lactate, and alanine aminotransferase (ALT) levels. Additionally, oxidative stress markers, such as reactive oxygen species (ROS) levels, superoxide dismutase (SOD) activity, and catalase activity and the formation of thiobarbituric acid-reactive substances, were investigated. The results revealed that the group fed a high-fat diet exhibited an increase in ROS production and SOD activity. In contrast, the group administered the high-fat diet and subjected to physical exercise demonstrated a notable reduction in visceral adipocyte area, hepatic steatosis levels, ALT levels, and SOD activity. These findings indicate that physical exercise has a positive effect on obesity and oxidative stress in zebrafish, providing promising evidence for future investigations in this field.

Exercise Reduces Glucose Intolerance, Cardiac Inflammation and Adipose Tissue Dysfunction in Psammomys obesus Exposed to Short Photoperiod and High Energy Diet.

Circadian disruption causes glucose intolerance, cardiac fibrosis, and adipocyte dysfunction in sand rats (Psammomys obesus). Exercise intervention can improve glucose metabolism, insulin sensitivity, adipose tissue function and protect against inflammation. We investigated the influence of exercise on male P. obesus exposed to a short photoperiod (5 h light:19 h dark) and high-energy diet. Exercise reduced glucose intolerance. Exercise reduced cardiac expression of inflammatory marker Ccl2 and Bax:Bcl2 apoptosis ratio. Exercise increased heart:body weight ratio and hypertrophy marker Myh7:Myh6, yet reduced Gata4 expression. No phenotypic changes were observed in perivascular fibrosis and myocyte area. Exercise reduced visceral adipose expression of inflammatory transcription factor Rela, adipogenesis marker Ppard and browning marker Ppargc1a, but visceral adipocyte size was unaffected. Conversely, exercise reduced subcutaneous adipocyte size but did not affect any molecular mediators. Exercise increased ZT7 Bmal1 and Per2 in the suprachiasmatic nucleus and subcutaneous Per2. Our study provides new molecular insights and histological assessments on the effect of exercise on cardiac inflammation, adipose tissue dysfunction and circadian gene expression in P. obesus exposed to short photoperiod and high-energy diet. These findings have implications for the protective benefits of exercise for shift workers in order to reduce the risk of diabetes and cardiovascular disease.

SGLT2 inhibitor canagliflozin reduces visceral adipose tissue in db/db mice by modulating AMPK/KLF4 signaling and regulating mitochondrial dynamics to induce browning

Obesity is characterized by excessive accumulation of adipose tissue (mainly visceral). The morphology and function of mitochondria are crucial for regulating adipose browning and weight loss. Research suggests that the SGLT2 inhibitor canagliflozin may induce weight loss through an unknown mechanism, particularly targeting visceral adipose tissue. While Krueppel-Like Factor 4 (KLF4) is known to be essential for energy metabolism and mitochondrial function, its specific impact on visceral adipose tissue remains unclear. We administered canagliflozin to db/db mice for 8 weeks, or exposed adipocytes to canagliflozin for 24 h. The expression levels of browning markers, mitochondrial dynamics, and KLF4 were assessed. Then we validated the function of KLF4 through overexpression in vivo and in vitro. Adenosine monophosphate-activated protein kinase (AMPK) agonists, inhibitors, and KLF4 si-RNA were employed to elucidate the relationship between AMPK and KLF4. The findings demonstrated that canagliflozin significantly decreased body weight in db/db mice and augmented cold-induced thermogenesis. Additionally, canagliflozin increased the expression of mitochondrial fusion-related factors while reducing the levels of fission markers in epididymal white adipose tissue. These consistent findings were mirrored in canagliflozin-treated adipocytes. Similarly, overexpression of KLF4 in both adipocytes and db/db mice yielded comparable results. In all, canagliflozin mitigates obesity in db/db mice by promoting the brown visceral adipocyte phenotype through enhanced mitochondrial fusion via AMPK/KLF4 signaling.

Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow

Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow upon estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); yet positively modulates leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased leptin secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu.

Molecules secreted by visceral adipocytes in patients with coronary atherosclerosis and insulin resistance

Aim. To study the association of adipocytokine levels with insulin resistance (IR) and stable/unstable plaques in patients with coronary atherosclerosis.Material and methods. This cross-sectional observational study included 109 men aged 38-79 years with class II-III stable angina pectoris without acute coronary syndrome (ACS), with coronary atherosclerosis verified by coronary angiography. Biochemical tests were carried out using the enzymatic method on a Konelab 30i analyzer at the Laboratory of Clinical Biochemical and Hormonal Studies of Internal Diseases of the Research Institute of Internal and Preventive Medicine — branch of the Federal Research Center Institute of Cytology and Genetics. All patients also underwent anthropometric examination.Results. Patients with coronary atherosclerosis and IR had higher levels of GIP by 1,4 times (p=0,005), GLP-1 by 1,7 times (p=0,032), IL-6 by 3,2 times (p=0,017), leptin by 2,3 times (p=0,001) and pancreatic polypeptide (PP) by 1,9 times (p=0,006). In patients with stable plaques and IR, leptin was 2 times higher, and PP was 1,7 times higher, compared to patients without IR. In patients with unstable plaques and IR, leptin and PP levels are 5,1 and 1,7 times higher, respectively, compared to the group of patients without IR. In patients with IR and stable plaques, PYY was 1,5 times higher than in patients with IR and unstable plaques, while the adiponectin level was 1,9 times higher. Logistic regression analysis demonstrated that PP is associated with IR in patients with unstable plaques.Conclusion. Patients with coronary atherosclerosis and IR had higher levels of GIP, GLP-1, IL-6, leptin and PP. Leptin and PP levels are higher in patients with both stable and unstable plaques and IR, and PYY and adiponectin levels are higher in patients with stable plaques and IR compared with patients without IR. PP is associated with IR in patients with unstable plaques.

The Influence of Subcutaneous and Visceral Adipocyte Geometries on Metabolic Parameters and Metabolic Regulating Hormones in Obese and Non-Obese Subjects

Adipose tissue plays a pivotal role in endocrine and metabolic homeostasis. This study aimed to compare subcutaneous and visceral adipocyte measurements, including area, shortest diameter, longest diameter, and perimeter, between groups of different metabolic profiles; and to determine correlations of adipocyte geometries with metabolic parameters and hormones in obese (n=20) and non-obese subjects (n=14). We hypothesized that geometries of subcutaneous and visceral adipocytes differ between groups with distinct metabolic conditions, and that their measurements correlate with obesity parameters, metabolic profiles, and hormones differently within subcutaneous and visceral adipocyte parameters as well as between obese and non-obese subjects. A total of 34 subjects were classified based on insulin resistance, using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) >2.3, and the presence of hypertension (HT), defined as systolic blood pressure (SBP)/diastolic blood pressure (DBP) ≥130/80 mmHg. These subjects underwent open abdominal surgery, with blood sample collection in a fasting state before the operation, and abdominal subcutaneous and omental (visceral) adipose tissue collection during the operation. Subjects with insulin resistance (n=6) and those with HT (n=15) both had a greater size of visceral adipocytes compared to those without insulin resistance (n=28) or HT (n=19), respectively; however, there were no significant differences in subcutaneous adipocyte size between the groups. For correlation analyses in obese subjects, subcutaneous adipocyte measurements exhibited significant positive correlations with visceral adipocyte measurements (R=0.592-0.630); while they showed significant negative correlations with cholesterol (R=-0.573) and serum visfatin (R=-0.610), all with p<0.05. Furthermore, in obese subjects, visceral adipocytes geometries were positively correlated with body weight, waist circumference, and hip circumference (R=0.575-R=0.607), all with p<0.05. In non-obese subjects, geometries of subcutaneous adipocytes were significantly positively correlated with body weight, BMI, waist circumference, and visceral adipocyte size (R=0.555-0.642); while were negatively correlated with serum adiponectin (R=(-0.608)-(-0.676)), all with p<0.05. Furthermore, in non-obese subjects, the measurements of visceral adipocytes were significantly positively correlated with body weight, BMI, serum leptin levels, serum leptin/adiponectin ratio, waist circumference, and DBP (R=0.555-0.836); while were negatively correlated with serum adiponectin (R=(-0.608)-(-0.647), all with p<0.05. These results suggest that hypertrophy of visceral adipocytes, rather than subcutaneous adipocytes, could contribute to insulin resistance and hypertension. Subcutaneous adipocyte size in obese subjects was not correlated with obesity parameters but was negatively correlated with cholesterol and visfatin levels potentially reflecting a protective effect or a compensatory mechanism in which an increase in subcutaneous fat might be a response to store excess lipids more safely when visceral fat capacity is limited. In non-obese subjects, visceral adipocyte geometries were positively correlated with DBP but inversely related to serum levels of adiponectin, an anti-inflammatory adipokine, indicating that larger adipocytes in non-obese individuals are not benign but indicative of early metabolic derangement. In conclusion, subcutaneous fat in obese individuals may represent a potentially protective effect or compensatory response to metabolic disturbance induced by excess visceral fat. In non-obese individuals, a larger visceral adipocyte size could signal early metabolic alterations, even in the absence of obesity. The research was funded by the Faculty of Medicine Siriraj Hospital Research Fund ((IO) R015332009). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Madecassoside modulates lipid metabolism in visceral adipocytes: exploring the browning, lipolysis, and lipogenesis mechanisms for potential obesity treatment.

Madecassoside (MA) is a triterpene derived from Centella asiatica that has been recognized for its antioxidant and anti-inflammatory properties in various disease models. However, its direct impact on cultured white adipocytes and the underlying mechanisms, mainly through gene knockdown, have not been thoroughly explored. Western blot analysis was utilized to assess the expression levels of various proteins, while oil red O staining was used to measure lipid deposition. The adipocyte shapes were confirmed using H&E staining. MA treatment enhanced browning and lipolysis in 3T3-L1 adipocytes and adipose tissue from experimental mice while suppressing lipogenesis. Furthermore, MA treatment increased the expression of PPARα and FGF21 in 3T3-L1 adipocytes as well as the secretion of FGF21 into the culture medium. Knockdown of PPARα or FGF21 using siRNA diminished the effects of MA on lipid metabolism in cultured adipocytes. These findings demonstrate that MA promotes thermogenic browning and lipolysis while inhibiting adipocyte lipogenesis, thus showing the potential for attenuating obesity. The study suggested that MA could be a viable therapeutic approach for treating obesity.

Tumoral acidosis promotes adipose tissue depletion by fostering adipocyte lipolysis

ObjectiveTumour progression drives profound alterations in host metabolism, such as adipose tissue depletion, an early event of cancer cachexia. As fatty acid consumption by cancer cells increases upon acidosis of the tumour microenvironment, we reasoned that fatty acids derived from distant adipose lipolysis may sustain tumour fatty acid craving, leading to the adipose tissue loss observed in cancer cachexia. MethodsTo evaluate the pro-lipolytic capacities of acid-exposed cancer cells, primary mouse adipocytes from subcutaneous and visceral adipose tissue were exposed to pH-matched conditioned medium from human and murine acid-exposed cancer cells (pH 6.5), compared to naive cancer cells (pH 7.4). To further address the role of tumoral acidosis on adipose tissue loss, a pH-low insertion peptide was injected into tumour-bearing mice, and tumoral acidosis was neutralised with a sodium bicarbonate buffer. Prolipolytic mediators were identified by transcriptomic approaches and validated on murine and human adipocytes. ResultsHere, we reveal that acid-exposed cancer cells promote lipolysis from subcutaneous and visceral adipocytes and that dampening acidosis in vivo inhibits adipose tissue depletion. We further found a set of well-known prolipolytic factors enhanced upon acidosis adaptation and unravelled a role for β-glucuronidase (GUSB) as a promising new actor in adipocyte lipolysis. ConclusionsTumoral acidosis promotes the mobilization of fatty acids derived from adipocytes via the release of soluble factors by cancer cells. Our work paves the way for therapeutic approaches aimed at tackling cachexia by targeting the tumour acidic compartment.

Gastric cancer and metabolic syndrome

Gastric cancer (GC), a prevalent disease in Asian countries, presents a substantial global health challenge. The risk factors for GC include Helicobacter pylori infection, diet, smoking, alcohol, and metabolic syndrome (MetS). This review meticulously examines the intricate connections between MetS and GC, focusing on visceral adipocytes, hormonal factors, obesity, and their impact on survival outcomes. Visceral adipocytes, which secrete inflammatory cytokines and hormones, play a pivotal role in influencing cancer development. Hormonal factors demonstrate nuanced associations with specific GC subtypes, underscoring the complexity of their impact. Large-scale studies exploring obesity-related factors reveal sex-specific nuances and underscore the importance of considering overall weight and body composition. Furthermore, the review explores the impact of eradication therapy for H. pylori infection, which is the most significant factor in the onset of GC, on the components of MetS. Additionally, the influence of MetS on postoperative outcomes and survival in GC patients highlights the interplay between therapeutic interventions and lifestyle factors. This comprehensive exploration sheds light on the multifaceted relationship between MetS and GC, providing valuable insights for future research and preventive strategies.

Gene and lncRNA Profiling of ω3/ω6 Polyunsaturated Fatty Acid-Exposed Human Visceral Adipocytes Uncovers Different Responses in Healthy Lean, Obese and Colorectal Cancer-Affected Individuals.

Colorectal cancer (CRC) is a major life-threatening disease, being the third most common cancer and a leading cause of death worldwide. Enhanced adiposity, particularly visceral fat, is a major risk factor for CRC, and obesity-associated alterations in metabolic, inflammatory and immune profiles in visceral adipose tissue (VAT) strongly contribute to promoting or sustaining intestinal carcinogenesis. The role of diet and nutrition in obesity and CRC has been extensively demonstrated, and AT represents the main place where diet-induced signals are integrated. Among the factors introduced with diet and processed or enriched in AT, ω3/ω6 polyunsaturated fatty acids (PUFAs) are endowed with pro- or anti-inflammatory properties and have been shown to exert either promoting or protective roles in CRC. In this study, we investigated the impact of ex vivo exposure to the ω3 and ω6 PUFAs docosahexaenoic and arachidonic acids on VAT adipocyte whole transcription in healthy lean, obese and CRC-affected individuals. High-throughput sequencing of protein-coding and long non-coding RNAs allowed us to identify specific pathways and regulatory circuits controlled by PUFAs and highlighted an impaired responsiveness of obese and CRC-affected individuals as compared to the strong response observed in healthy lean subjects. This further supports the role of healthy diets and balanced ω3/ω6 PUFA intake in the primary prevention of obesity and cancer.

Polyphenol-rich black currant and cornelian cherry juices ameliorate metabolic syndrome induced by a high-fat high-fructose diet in Wistar rats

Diets high in fat and sugar lead to metabolic syndrome (MetS) and related chronic diseases. We investigated the effects of commercially available, cold-pressed polyphenol-rich black currant (BC) and cornelian cherry (CC) juices on the prevention of MetS in Wistar rats induced by a 10-weeks high-fat high-fructose (HFF) diet. Juice consumption, either BC or CC, with a HFF diet resulted in lower serum triglycerides compared to only the HFF consumption. Both juices also mitigated the effects of HFF on the liver, pancreas, and adipose tissue, by preserving liver and pancreas histomorphology and reducing visceral fat and adipocyte size. Furthermore, supplementation with both juices reduced glucagon and up-regulated insulin expression in the pancreas of the rats on the HFF diet, whereas the BC also showed improved glucose regulation. BC juice also reduced the expression of IL-6 and hepatic inflammation compared to the group only on HFF diet. Both juices, especially BC, could be a convenient solution for the prevention of MetS in humans.

Comparison of the effects of renal denervation at early or advanced stages of hypertension on cardiac, renal, and adipose tissue pathology in Dahl salt-sensitive rats

Renal denervation (RDN) has emerged as a novel therapy for drug-resistant hypertension. We here examined the effects of RDN at early versus advanced stages of hypertension on blood pressure and organ pathology in rats with salt-sensitive hypertension. Dahl salt-sensitive (DahlS) rats fed an 8% NaCl diet from 6 weeks of age were subjected to RDN (surgical ablation and application of 10% phenol in ethanol) or sham surgery at 7 (early stage) or 9 (advanced stage) weeks and were studied at 12 weeks. RDN at early or advanced stages resulted in a moderate lowering of blood pressure. Although RDN at neither stage affected left ventricular (LV) and cardiomyocyte hypertrophy, it ameliorated LV diastolic dysfunction, fibrosis, and inflammation at both stages. Intervention at both stages also attenuated renal injury as well as downregulated the expression of angiotensinogen and angiotensin-converting enzyme (ACE) genes and angiotensin II type 1 receptor protein in the kidney. Furthermore, RDN at both stages inhibited proinflammatory gene expression in adipose tissue. The early intervention reduced both visceral fat mass and adipocyte size in association with downregulation of angiotensinogen and ACE gene expression. In contrast, the late intervention increased fat mass without affecting adipocyte size as well as attenuated angiotensinogen and ACE gene expression. Our results thus indicate that RDN at early or late stages after salt loading moderately alleviated hypertension and substantially ameliorated cardiac and renal injury and adipose tissue inflammation in DahlS rats. They also suggest that cross talk among the kidney, cardiovascular system, and adipose tissue may contribute to salt-sensitive hypertension.Supposed mechanism for the beneficial effects of RDN on hypertension and target organ damage in DahlS rats. RDN at early or late stages after salt loading moderately alleviated hypertension and substantially ameliorated renal injury in DahlS rats. Cross talk among the kidney, cardiovascular system, and adipose tissue possibly mediated by circulating RAS may contribute to salt-sensitive hypertension. LV; left ventricular, NE; norepinephrine, RAS; renin-angiotensin system, RDN; renal denervation.

Dopamine D2 receptor antagonist counteracts hyperglycemia and insulin resistance in diet-induced obese male mice.

Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity.

Relationship between adipokines and androgens in children and young adults with congenital adrenal hyperplasia.

Children and young adults with congenital adrenal hyperplasia (CAH) are at increased risk of obesity and insulin resistance. There is evidence that children with CAH have increased visceral adiposity, which has been linked to metabolic syndrome and cardiovascular disease (CVD). The adipokine adiponectin has been shown to correlate with reduced metabolic risk, whereas the adipokines visfatin and leptin have been linked to visceral fat and adipocyte inflammation and can serve as biomarkers of increased metabolic risk. Few studies to date have characterized adipokine levels in children and young adults with congenital adrenal hyperplasia. We sought to investigate the relationship between adiponectin, leptin and visfatin levels to metabolic risk factors and androgen levels in children and young adults with CAH. Fasting blood was obtained for visfatin, leptin, adiponectin, glucose, insulin, CRP, lipid panel, total cholesterol (TC), triglycerides (TG) and HbA1c, as well as standard laboratory tests to assess adrenal control, from children with CAH due to 21-hydroxylase deficiency. HOMA-IR was calculated based on fasting glucose and insulin. Anthropomorphic measurements of BMI and waist-to-hip ratio were also obtained. Adiponectin and androstenedione were inversely correlated (R = -0.57, p =0.016). There was a positive correlation between leptin and BMI percentile (R = 0.63, p <0.001) as well as leptin and HOMA-IR (R = 0.63, p <0.01). Glucocorticoid dose had a positive correlation with HOMA-IR (R=0.56, p = 0.021). Visfatin was inversely correlated with HDL cholesterol (R = -0.54, p = 0.026) and total cholesterol (R = -0.49, p <0.05). Overweight children and young adults had a significantly higher leptin (p = 0.02) and HOMA-IR (p=0.001) than non-overweight children and young adults. The inverse relationship between adiponectin and androstenedione suggests that better CAH control can reduce the risk of insulin resistance and metabolic syndrome. However, a high glucocorticoid dose appears to increase the risk of insulin resistance, underscoring the delicate balance required when treating CAH.

Lipid Storage, Lipolysis, and Lipotoxicity in Obesity.

The ratio of free fatty acid (FFA) turnover decreases significantly with the expansion of white adipose tissue. Adipose tissue and dietary saturated fatty acid levels significantly correlate with an increase in fat cell size and number. The G0/G1 switch gene 2 increases lipid content in adipocytes and promotes adipocyte hypertrophy through the restriction of triglyceride (triacylglycerol: TAG) turnover. Hypoxia in obese adipose tissue due to hypertrophic adipocytes results in excess deposition of extracellular matrix (ECM) components. Cluster of differentiation (CD) 44, as the main receptor of the extracellular matrix component regulates cell-cell and cell-matrix interactions including diet-induced insulin resistance. Excess TAGs, sterols, and sterol esters are surrounded by the phospholipid monolayer surface and form lipid droplets (LDs). Once LDs are formed, they grow up because of the excessive amount of intracellular FFA stored and reach a final size. The ratio of FFA turnover/lipolysis decreases significantly with increases in the degree of obesity. Dysfunctional adipose tissue is unable to expand further to store excess dietary lipids, increased fluxes of plasma FFAs lead to ectopic fatty acid deposition and lipotoxicity. Reduced neo-adipogenesis and dysfunctional lipid-overloaded adipocytes are hallmarks of hypertrophic obesity linked to insulin resistance. Obesity-associated adipocyte death exhibits feature of necrosis-like programmed cell death. Adipocyte death is a prerequisite for the transition from hypertrophic to hyperplastic obesity. Increased adipocyte number in obesity has life-long effects on white adipose tissue mass. The positive correlation between the adipose tissue volume and magnetic resonance imaging proton density fat fraction estimation is used for characterization of the obesity phenotype, as well as the risk stratification and selection of appropriate treatment strategies. In obese patients with type 2 diabetes, visceral adipocytes exposed to chronic/intermittent hyperglycemia develop a new microRNAs' (miRNAs') expression pattern. Visceral preadipocytes memorize the effect of hyperglycemia via changes in miRNAs' expression profile and contribute to the progression of diabetic phenotype. Nonsteroidal anti-inflammatory drugs, metformin, and statins can be beneficial in treating the local or systemic consequences of white adipose tissue inflammation. Rapamycin inhibits leptin-induced LD formation. Collectively, in this chapter, the concept of adipose tissue remodeling in response to adipocyte death or adipogenesis, and the complexity of LD interactions with the other cellular organelles are reviewed. Furthermore, clinical perspective of fat cell turnover in obesity is also debated.

Experimental periodontitis induced hypoadiponectinemia by IRE1α-mediated endoplasmic reticulum stress in adipocytes

BackgroudHypoadiponectinemia is the important cause of insulin resistance. Recent studies have shown that periodontitis is associated with hypoadiponectinemia. The purpose of this study was to investigate the effect of periodontitis-induced endoplasmic reticulum stress (ERS) in visceral adipocytes on hypoadiponectinemia.MethodsRat periodontitis models were established by local ligation with silk around the bilateral maxillary second molars. Porphyromonas gingivalis-lipopolysaccharid (P.g-LPS) was also used to stimulate the visceral adipocytes in vitro. The protein expression levels of glucose regulated protein 78 (GRP78), inositol-requiring protein 1α (IRE1α), protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6) and adiponectin were detected. IRE1α lentiviruses were transfected into visceral adipocytes in vitro, and an IRE1α inhibitor (KIRA6) was injected in epididymal adipose tissue of rats to detect and verify the effect of ERS on adiponectin expression in visceral adipocytes in vivo.ResultsHypoadiponectinemia was observed in periodontitis rat, and the expression levels of ERS key proteins GRP78 and the phosphorylation levels of IRE1α (p-IRE1α)/IRE1α in visceral adipocytes were increased, while the expression levels of adiponectin protein were decreased. After KIRA6 injection into epididymal adipose tissue of rats with periodontitis, adiponectin levels in visceral adipocytes increased, and serum adiponectin levels recovered to a certain extent. The protein expression levels of GRP78 and p-IRE1α/IRE1α were increased and adiponectin protein expression was decreased in P.g-LPS-induced visceral adipocytes. Overexpression of IRE1α further inhibited adiponectin expression in P.g-LPS-stimulated visceral adipocytes, and conversely, IRE1α inhibition restored adiponectin expression.ConclusionsOur findings suggest that periodontitis induces ERS in visceral adipocytes leading to hypoadiponectinemia. IRE1α is a key protein regulating adiponectin expression in visceral adipocytes.

Fenofibrate alleviates insulin resistance by reducing tissue inflammation in obese ovariectomized mice

BackgroundFenofibrate is a hypolipidemic peroxisome proliferator-activated receptor α (PPARα) agonist used clinically to reduce hypercholesterolemia and hypertriglyceridemia.ObjectiveWe investigated the effects of fenofibrate on insulin resistance and tissue inflammation in a high-fat diet (HFD)-fed ovariectomized (OVX) C57BL/6J mice, a mouse model of obese postmenopausal women.MethodsFemale OVX mice were randomly divided into 3 groups and received a low-fat diet, an HFD, or an HFD supplemented with 0.05% (w/w) fenofibrate for 9 weeks. Parameters of insulin resistance and tissue inflammation were measured using blood analysis, histological analysis, immunohistochemistry, and quantitative real-time polymerase chain reaction.ResultsWhen fenofibrate was administered to HFD-fed OVX mice for 9 weeks, we observed reductions in body weight gain, adipose tissue mass, and the size of visceral adipocytes without the change of food intake. Fenofibrate improved mild hyperglycemia, severe hyperinsulinemia, and glucose tolerance in these mice. It also reduced pancreatic islet size and insulin-positive β-cell area to levels similar to those in OVX mice fed a low-fat diet. Concomitantly, administration of fenofibrate not only suppressed pancreatic lipid accumulation but also decreased CD68-positive macrophages in both the pancreas and visceral adipose tissue. Treatment with fenofibrate reduced tumor necrosis factor α (TNFα) mRNA levels in adipose tissue and lowered serum TNFα levels.ConclusionThese results suggest that fenofibrate treatment attenuates insulin resistance in part by reducing tissue inflammation and TNFα expression in HFD-fed OVX mice.