Lemon Balm and Corn Silk Extracts Mitigate High-Fat Diet-Induced Obesity in Mice

Lemon balm and corn silk are valuable medicinal herbs, which exhibit variety of beneficial effects for human health. The present study explored the anti-obesity effects of a mixture of lemon balm and corn silk extracts (M-LB/CS) by comparison with the effects of single herbal extracts in high-fat diet (HFD)-induced obesity in mice. HFD supplementation for 84 days increased the body weight, the fat mass density, the mean diameter of adipocytes, and the thickness of fat pads. However, oral administration of M-LB/CS significantly alleviated the HFD-mediated weight gain and adipocyte hypertrophy without affecting food consumption. Of the various combination ratios of M-LB/CS tested, the magnitude of the decreases in weight gain and adipocyte hypertrophy by administration of 1:1, 1:2, 2:1, and 4:1 (w/w) M-LB/CS was more potent than that by single herbal extracts alone. In addition, M-LB/CS reduced the HFD-mediated increases in serum cholesterol, triglyceride, and low-density lipoprotein, prevented the reduction in serum high-density lipoprotein, and facilitated fecal excretion of cholesterol and triglyceride. Moreover, M-LB/CS mitigated the abnormal changes in specific mRNAs associated with lipogenesis and lipolysis in the adipose tissue. Furthermore, M-LB/CS reduced lipid peroxidation by inhibiting the HFD-mediated reduction in glutathione, catalase, and superoxide dismutase. Therefore, M-LB/CS is a promising herbal mixture for preventing obesity.

Metabolic Effects of CCN5/WISP2 Gene Deficiency and Transgenic Overexpression in Mice

CCN5/WISP2 is a matricellular protein, the expression of which is under the regulation of Wnt signaling and IGF-1. Our initial characterization supports the notion that CCN5 might promote the proliferation and survival of pancreatic β-cells and thus improve the metabolic profile of the animals. More recently, the roles of endogenous expression of CCN5 and its ectopic, transgenic overexpression on metabolic regulation have been revealed through two reports. Here, we attempt to compare the experimental findings from those studies, side-by-side, in order to further establish its roles in metabolic regulation. Prominent among the discoveries was that a systemic deficiency of CCN5 gene expression caused adipocyte hypertrophy, increased adipogenesis, and lipid accumulation, resulting in insulin resistance and glucose intolerance, which were further exacerbated upon high-fat diet feeding. On the other hand, the adipocyte-specific and systemic overexpression of CCN5 caused an increase in lean body mass, improved insulin sensitivity, hyperplasia of cardiomyocytes, and increased heart mass, but decreased fasting glucose levels. CCN5 is clearly a regulator of adipocyte proliferation and maturation, affecting lean/fat mass ratio and insulin sensitivity. Not all results from these models are consistent; moreover, several important aspects of CCN5 physiology are yet to be explored.

Impact of Bariatric Surgery on Adipose Tissue Biology

Bariatric surgery (BS) procedures are actually the most effective intervention to help subjects with severe obesity achieve significant and sustained weight loss. White adipose tissue (WAT) is increasingly recognized as the largest endocrine organ. Unhealthy WAT expansion through adipocyte hypertrophy has pleiotropic effects on adipocyte function and promotes obesity-associated metabolic complications. WAT dysfunction in obesity encompasses an altered adipokine secretome, unresolved inflammation, dysregulated autophagy, inappropriate extracellular matrix remodeling and insufficient angiogenic potential. In the last 10 years, accumulating evidence suggests that BS can improve the WAT function beyond reducing the fat depot sizes. The causal relationships between improved WAT function and the health benefits of BS merits further investigation. This review summarizes the current knowledge on the short-, medium- and long-term outcomes of BS on the WAT composition and function.

Transcriptome and fatty-acid signatures of adipocyte hypertrophy and its non-invasive MR-based characterization in human adipose tissue

Adipose tissue is an organ with great plasticity and its hypertrophic expansion is associated with adipocyte dysfunction. How changes in adipocyte morphology are linked to gene expression and which cellular functions are affected remains elusive. We show that adipocyte hypertrophy is associated with transcriptomic changes using RNA-Seq data obtained from adipose tissue and size-separated adipocytes. Genes involved in oxidative phosphorylation, protein biosynthesis and fatty acid metabolism were down-regulated in large adipocytes while genes involved in inflammation were upregulated. For mitochondrial function, a reduction in the expression of thermogenesis related genes and estimated brown/beige adipocyte content was observed in individuals with large adipocytes. As a novel finding the total adipose tissue fatty acid composition was dependent on cell size and depot. MR spectroscopy methods for clinical scanning were developed to characterize adipocyte size and fatty acid composition in a fast and non-invasive manner. Together, the present data provides mechanistic insights on how adipocyte hypertrophy contributes to the manifestation of metabolic disease at the molecular and cellular level. MR spectroscopy was identified as a promising technique for an in-parallel assessment of adipose morphology and fatty acid composition allowing to translate our findings into an improved, non-invasive phenotyping of adipose tissue.

Contribution of markers of adiposopathy and adipose cell size in predicting insulin resistance markers in women of varying age and adiposity

Markers of adipose tissue (AT) dysfunctions, such as adipocyte hypertrophy, macrophage infiltration and secretory adiposopathy (low plasma adiponectin/leptin, A/L, ratio), associate with metabolic disorders. However, no study has compared the relative contribution of these markers to cardiometabolic risk in women of varying age and adiposity. Body composition, regional AT distribution, lipid-lipoprotein profile, glucose homeostasis and plasma A and L levels were determined in 67 women (age: 40-62 years; BMI: 17-41 kg/m2). Expression of macrophage infiltration marker CD68 and adipocyte size were measured from subcutaneous abdominal (SCABD) and omental (OME) fat samples. AT dysfunction markers were correlated with most lipid-lipoprotein levels such as TAGs (-0.36<rho<0.46; 0.0005<p<0.05), except OME CD68 expression which was negatively related to HDL-cholesterol. The A/L ratio was negatively associated with fasting insulinemia and HOMA-IR (-0.60<rho<-0.63; p<0.0001), while SCABD or OME adipocyte size and SCABD CD68 expression were positively related to these variables (0.39<rho<0.59; p<0.01). Multiple regression analyses including these markers and triacylglycerol (TAG) levels revealed that the A/L ratio was the only predictor of fasting insulinemia and HOMA-IR (partial R2=0.31-0.33; 0.000<p<0.005) in the model with TAGs and CD68 expression. However, the contribution of the A/L ratio was supplanted by adipose cell size in the model where the latter replaced TAGs. Combination of tertiles of largest adipocyte size and lowest A/L ratio showed the highest HOMA-IR. Taken together, our results show that adipocyte hypertrophy combined with reduced A/L ratio was related to increased IR, suggesting an independent contribution of both markers to the variance of cardiometabolic risk.

High-Fat and Combined High-Fat and Sucrose Diets Promote Cardiac Oxidative Stress Independent of Nox2 Redox Regulation and Obesity in Rats

BACKGROUND/AIMS: Oxidative stress is associated with cardiometabolic alterations, and the involvement of excess glucose and fatty acids has been demonstrated in this process. Thus, the aim of this study was to investigate the effects of different hypercaloric diets on cardiac oxidative stress. METHODS: Wistar rats were randomized into four groups: control (C), high-sucrose (HS), high-fat (HF), and high-fat with sucrose (HFS). Nutritional assessment, food profiles, histological analysis, comorbidities, and cardiovascular characteristics were determined. Cardiac oxidative stress was analyzed by malondialdehyde (MDA) and carbonylated proteins, and the cardiac protein expression levels of type 1 angiotensin receptor (AT-1), nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2), superoxide dismutase (SOD 1 e 2), glutathione peroxidase (GPX), and catalase (CAT) were determined by western blot. RESULTS: The HF group showed an increase in adiposity; however, it did not present adipocyte hypertrophy and comorbidities. Cardiac MDA and carbonylated protein levels were higher in the HF and HFS compared with the C group. The levels of oxidant and antioxidant proteins showed no difference between the groups. CONCLUSION: HF and HFS dietary interventions promoted cardiac oxidative stress, in the presence and absence of obesity, respectively. However, this process was neither mediated by the pro-oxidants AT1 and Nox2, nor by the quantitative reduction of antioxidant enzymes.

Breast Cancer Endocrine Therapy Promotes Weight Gain With Distinct Adipose Tissue Effects in Lean and Obese Female Mice

Breast cancer survivors treated with tamoxifen and aromatase inhibitors report weight gain and have an elevated risk of type 2 diabetes, especially if they have obesity. These patient experiences are inconsistent with, preclinical studies using high doses of tamoxifen which reported acute weight loss. We investigated the impact of breast cancer endocrine therapies in a preclinical model of obesity and in a small group of breast adipose tissue samples from women taking tamoxifen to understand the clinical findings. Mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in mesenchymal stem cells from adipose tissue, endocrine therapy was associated with adipose accumulation and more preadipocytes compared with estrogen-treated control mice but resulted in fewer adipocyte progenitors only in the context of HFHS. Analysis of subcutaneous adipose stromal cells revealed diet- and treatment-dependent effects of endocrine therapies on various cell types and genes, illustrating the complexity of adipose tissue estrogen receptor signaling. Breast cancer therapies supported adipocyte hypertrophy and associated with hepatic steatosis, hyperinsulinemia, and glucose intolerance, particularly in obese females. Current tamoxifen use associated with larger breast adipocyte diameter only in women with obesity. Our translational studies suggest that endocrine therapies may disrupt adipocyte progenitors and support adipocyte hypertrophy, potentially leading to ectopic lipid deposition that may be linked to a greater type 2 diabetes risk. Monitoring glucose tolerance and potential interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

Smad2/3 Activation Regulates Smad1/5/8 Signaling via a Negative Feedback Loop to Inhibit 3T3-L1 Adipogenesis

Adipose tissues (AT) expand in response to energy surplus through adipocyte hypertrophy and hyperplasia. The latter, also known as adipogenesis, is a process by which multipotent precursors differentiate to form mature adipocytes. This process is directed by developmental cues that include members of the TGF-β family. Our goal here was to elucidate, using the 3T3-L1 adipogenesis model, how TGF-β family growth factors and inhibitors regulate adipocyte development. We show that ligands of the Activin and TGF-β families, several ligand traps, and the SMAD1/5/8 signaling inhibitor LDN-193189 profoundly suppressed 3T3-L1 adipogenesis. Strikingly, anti-adipogenic traps and ligands engaged the same mechanism of action involving the simultaneous activation of SMAD2/3 and inhibition of SMAD1/5/8 signaling. This effect was rescued by the SMAD2/3 signaling inhibitor SB-431542. By contrast, although LDN-193189 also suppressed SMAD1/5/8 signaling and adipogenesis, its effect could not be rescued by SB-431542. Collectively, these findings reveal the fundamental role of SMAD1/5/8 for 3T3-L1 adipogenesis, and potentially identify a negative feedback loop that links SMAD2/3 activation with SMAD1/5/8 inhibition in adipogenic precursors.

Sexual Dimorphism in Changes That Occur in Tissues, Organs and Plasma during the Early Stages of Obesity Development

Despite obesity being a major health concern, information on the early clinical changes that occur in plasma and tissues during obesity development and the influence of sexual dimorphism is lacking. This study investigated changes in tissue and organ histology, macrophage infiltration, plasma hormones, lipid, and chemokine and cytokine levels in mice fed on a high fat diet for 11-weeks. An increase in adiposity, accompanied by adipocyte hypertrophy and macrophage infiltration, was observed to be significantly greater in males than females. Important changes in cell morphology and histology were noted in the lungs, liver, kidney, spleen, and heart, which may indicate early signs for developing obesity associated comorbidities. Leptin, but not adiponectin, was significantly altered during weight gain. Additionally, leptin, but not adiposity, correlated with insulin levels. Interestingly, GM-CSF, TNFα, and IL-12 (p70) were not produced in the early stages of obesity development. Meanwhile, the production of MCP-1, IP-10, RANTES, IL-10, IL-6, KC, and IL-9 were greatly influenced by sexual dimorphism. Importantly, IL-6/IL-10 axis of anti-inflammatory cytokine regulation was observed only in females and may account for their significantly lower weight gain compared to males. This study provides new knowledge on how sexual dimorphism may influence the development of obesity and associated comorbidities.