Identification of Mfn2-S249 as a Phosphoregulatory Switch of Mitochondrial Fusion Dynamics

Mitochondrial remodeling is a fundamental process underlying cellular respiration and metabolism. Here we report TAK1 as a direct regulator of mitochondrial fusion. TAK1 is activated by a variety of mitogenic factors, cytokines and environmental stimuli, which we find induces rapid fragmentation through Mfn2 inactivation. TAK1 phosphorylates Mfn2 at Ser249, which inhibits the binding of GTP required for Mfn trans-dimerization and mitochondrial membrane fusion. Accordingly, expression of Mfn2-S249 phosphomimetics (Mfn2-E/D) constitutively promote fission whereas alanine mutant (Mfn2-A) yields hyperfused mitochondria and increased bioenergetics in cells. In mice, Mfn2-E knock-in yields embryonic lethality in homozygotes whereas heterozygotes are viable but exhibit increased visceral fat accumulation despite normal body weight and cognitive/motor functions compared to wildtype and Mfn2-A mice. Mature white adipocytes isolated from mutant mice reveal cell-autonomous TAK1-related effects on mitochondrial remodeling and lipid metabolism. These results identify Mfn2-S249 as a dynamic phosphoregulatory switch of mitochondrial fusion during development and energy homeostasis.

Genomic Analysis of Visceral Fat Accumulation in Holstein Cows

Visceral fat is related to important metabolic processes, including insulin sensitivity and lipid mobilization. The goal of this study was to identify individual genes, pathways, and molecular processes implicated in visceral fat deposition in dairy cows. Data from 172 genotyped Holstein cows classified at slaughterhouse as having low (n = 77; omental fold <5 mm in thickness and minimum fat deposition in omentum) or high (n = 95; omental fold ≥20 mm in thickness and marked fat deposition in omentum) omental fat were analyzed. The identification of regions with significant additive and non-additive genetic effects was performed using a two-step mixed model-based approach. Genomic scans were followed by gene-set analyses in order to reveal the genetic mechanisms controlling abdominal obesity. The association mapping revealed four regions located on BTA19, BTA20 and BTA24 with significant additive effects. These regions harbor genes, such as SMAD7, ANKRD55, and the HOXB family, that are implicated in lipolysis and insulin tolerance. Three regions located on BTA1, BTA13, and BTA24 showed marked non-additive effects. These regions harbor genes MRAP, MIS18A, PRNP and TSHZ1, that are directly implicated in adipocyte differentiation, lipid metabolism, and insulin sensitivity. The gene-set analysis revealed functional terms related to cell arrangement, cell metabolism, cell proliferation, cell signaling, immune response, lipid metabolism, and membrane permeability, among other functions. We further evaluated the genetic link between visceral fat and two metabolic disorders, ketosis, and displaced abomasum. For this, we analyzed 28k records of incidence of metabolic disorders from 14k cows across lactations using a single-step genomic BLUP approach. Notably, the region on BTA20 significantly associated with visceral fat deposition was also associated with the incidence of displaced abomasum. Overall, our findings suggest that visceral fat deposition in dairy cows is controlled by both additive and non-additive effects. We detected at least one region with marked pleiotropic effects affecting both visceral fat accumulation and displaced abomasum.

MXD3 Promotes Obesity and the Androgen Receptor Signaling Pathway in Gender-Disparity Hepatocarcinogenesis

Obesity is closely linked to metabolic diseases, particularly non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD), ultimately leading to hepatocellular carcinoma (HCC). However, the molecular mechanisms of NASH-associated HCC (NAHCC) remain elusive. To explore the impact of Max dimerization protein 3 (MXD3), a transcription factor that regulates several cellular functions in disorders associated with metabolic diseases, we conditionally expressed Mxd3 proteins using Tet-on mxd3 transgenic zebrafish (MXs) with doxycycline (MXs + Dox) or without doxycycline (MXs − Dox) treatment. Overexpression of global MXD3 (gMX) or hepatic Mxd3 (hMX) was associated with obesity-related NAFLD pathophysiology in gMX + Dox, and liver fibrosis and HCC in hMX + Dox. Oil Red O (ORO)-stained signals were seen in intravascular blood vessels and liver buds of larval gMX + Dox, indicating that Mxd3 functionally promotes lipogenesis. The gMX + Dox-treated young adults exhibited an increase in body weight and visceral fat accumulation. The hMX + Dox-treated young adults showed normal body characteristics but exhibited liver steatosis and NASH-like phenotypes. Subsequently, steatohepatitis, liver fibrosis, and NAHCC were found in 6-month-old gMX + Dox adults compared with gMX − Dox adults at the same stage. Overexpression of Mxd3 also enhanced AR expression accompanied by the increase of AR-signaling pathways resulting in hepatocarcinogenesis in males. Our results demonstrate that global actions of Mxd3 are central to the initiation of obesity in the gMX zebrafish through their effects on adipogenesis and that MXD3 could serve as a therapeutic target for obesity-associated liver diseases.

Regulation of p27 and Cdk2 Expression in Different Adipose Tissue Depots in Aging and Obesity

Aging usually comes associated with increased visceral fat accumulation, reaching even an obesity state, and favoring its associated comorbidities. One of the processes involved in aging is cellular senescence, which is highly dependent on the activity of the regulators of the cell cycle. The aim of this study was to analyze the changes in the expression of p27 and cdk2 in different adipose tissue depots during aging, as well as their regulation by obesity in mice. Changes in the expression of p27 and CDK2 in visceral and subcutaneous white adipose tissue (WAT) biopsies were also analyzed in a human cohort of obesity and type 2 diabetes. p27, but not cdk2, exhibits a lower expression in subcutaneous than in visceral WAT in mice and humans. p27 is drastically downregulated by aging in subcutaneous WAT (scWAT), but not in gonadal WAT, of female mice. Obesity upregulates p27 and cdk2 expression in scWAT, but not in other fat depots of aged mice. In humans, a significant upregulation of p27 was observed in visceral WAT of subjects with obesity. Taken together, these results show a differential adipose depot-dependent regulation of p27 and cdk2 in aging and obesity, suggesting that p27 and cdk2 could contribute to the adipose-tissue depot’s metabolic differences. Further studies are necessary to fully corroborate this hypothesis.

Update on Cardiovascular Risk and Obesity in Psoriatic Arthritis

PsA is characterized by a high prevalence of cardiovascular (CV) comorbidities. Recognizing these comorbidities is critical due to their influence on the quality of life and the choice of therapy. Imaging techniques also play an important role in the evaluation of the CV risk in psoriatic disease, improving the prediction of CV events when combined with clinical scores as a predictive tool. Meta-analyses point to a significant reduction in the incidence of CV events associated with the suppression of inflammatory activity when using systemic therapies. Consequently, the mortality rate in PsA patients has fallen in the last 40 years and is now similar to that of the general population, including cardiovascular causes. Obesity is an especially relevant CV comorbidity in patients with psoriatic disease, most of whom are overweight/obese. Body mass index (BMI) is a risk factor for PsA and a causal relationship with psoriasis has been demonstrated by Mendelian randomized studies. The study of fat distribution shows that patients with psoriasis are characterized by visceral fat accumulation, which correlates with CV risk measurements. These findings suggest that approaches to the prevention and treatment of psoriatic disease might come from targeting adiposity levels, in addition to the immune pathways. Weight loss treatment with low energy diets in patients with PsA has been associated with significant improvements in disease activity. Novel strategies using a multimorbidity approach, focused more on patients outcomes, are necessary to better address comorbidities, improve clinical outcomes and the quality of life of patients with psoriatic disease.

Visceral Fat Accumulation Is Related to Impaired Pancreatic Blood Perfusion and Beta-Cell Dysfunction in Obese Women

<b><i>Aims/Hypothesis:</i></b> Beta-cell failure plays a fundamental role in type 2 diabetes mellitus (T2DM) development. It has been shown that the beta-cells are among the most sensitive to hypoxia. We aimed to analyze whether decrease in pancreatic perfusion relates to 1/decline in beta-cell function and 2/visceral fat accumulation in patients with T2DM. <b><i>Methods:</i></b> Fifteen women with T2DM on metformin therapy alone and fifteen women of comparable age and BMI without prediabetes/diabetes were cross-sectionally examined: clinical and anthropometric examination, fast sampled intravenous glucose tolerance test (FSIVGTT), dynamic contrast-enhanced magnetic resonance imaging to assess pancreatic perfusion (area under the curve of postcontrast saturation, AUC_TSIC), and visceral adiposity (VAT, calculated from transverse sections at the level L2–L5 vertebrae). <b><i>Results:</i></b> Pancreatic blood perfusion (AUC_TSIC) did not differ between groups (<i>p</i> = 0.273), but it negatively correlated with BMI (<i>r</i> = −0.434, <i>p</i> = 0.017), WHR (<i>r</i> = −0.411, <i>p</i> = 0.024), and VAT (<i>r</i> = −0.436, <i>p</i> = 0.016) in both groups. Moreover, AUC_TSIC in the head of the pancreas negatively correlated with the level of fasting glycemia (<i>r</i> = −0.401, <i>p</i> = 0.028) and HOMA-IR (<i>r</i> = −0.376, <i>p</i> = 0.041). <b><i>Discussion/Conclusion:</i></b> We showed that decreased pancreatic perfusion did not relate to beta-cell dysfunction in early stages of T2DM development, but it was related to VAT, insulin resistance, and higher fasting glycemia. Furthermore, lower pancreatic perfusion was related to VAT, insulin resistance, and higher fasting glycemia.

The Sick Adipose Tissue: New Insights Into Defective Signaling and Crosstalk With the Myocardium

Adipose tissue (AT) biology is linked to cardiovascular health since obesity is associated with cardiovascular disease (CVD) and positively correlated with excessive visceral fat accumulation. AT signaling to myocardial cells through soluble factors known as adipokines, cardiokines, branched-chain amino acids and small molecules like microRNAs, undoubtedly influence myocardial cells and AT function via the endocrine-paracrine mechanisms of action. Unfortunately, abnormal total and visceral adiposity can alter this harmonious signaling network, resulting in tissue hypoxia and monocyte/macrophage adipose infiltration occurring alongside expanded intra-abdominal and epicardial fat depots seen in the human obese phenotype. These processes promote an abnormal adipocyte proteomic reprogramming, whereby these cells become a source of abnormal signals, affecting vascular and myocardial tissues, leading to meta-inflammation, atrial fibrillation, coronary artery disease, heart hypertrophy, heart failure and myocardial infarction. This review first discusses the pathophysiology and consequences of adipose tissue expansion, particularly their association with meta-inflammation and microbiota dysbiosis. We also explore the precise mechanisms involved in metabolic reprogramming in AT that represent plausible causative factors for CVD. Finally, we clarify how lifestyle changes could promote improvement in myocardiocyte function in the context of changes in AT proteomics and a better gut microbiome profile to develop effective, non-pharmacologic approaches to CVD.

Liraglutide may affect visceral fat accumulation in diabetic rats via changes in FTO, AMPK, and AKT expression

Purpose The aim of this study is to explore the effects of liraglutide (LRG) on the expression of FTO, AMPK, and AKT in the visceral adipose tissues of obese and diabetic rats and the underlying mechanisms thereof. Methods Thirty SPF-grade, male SD rats were randomly divided into the healthy control, diabetic model (DM), and DM + LRG groups. The DM and DM + LRG groups were administered normal saline and LRG (0.6 mg/kg/d), respectively. After 12 weeks, the body weight of the rats was measured, and their visceral adipose tissues were collected and weighed; the levels of serum biochemical indicators and FTO, AMPK, and AKT in these tissues were then measured using qRT-PCR and western blotting. Results Compared to the control group, the body weight and visceral fat accumulation and blood glucose, TG, TC, and LDL-C levels increased significantly, while the HDL-C levels decreased significantly, in the DM group (p < 0.05). After LRG treatment, the HDL-C levels increased significantly, but the levels of the other indicators decreased significantly (p < 0.05). Compared to the control group, the visceral adipose tissue levels of FTO and AKT increased significantly, while the AMPK levels decreased significantly in the DM group (p < 0.05). After LRG treatment, the FTO and AKT levels decreased significantly, and the AMPK levels increased significantly (p < 0.05). Conclusion LRG may activate and inhibit the AMPK and AKT pathways, respectively, and decrease FTO expression, thereby alleviating abdominal obesity in type 2 diabetes.

Association between Visceral Fat and Brain Structural Changes or Cognitive Function

Visceral fat accumulation is an independent risk factor for cardiovascular disease and mortality. Visceral fat is a causal risk factor for hypertension and type 2 diabetes, which was reported as one of the risk factors for dementia. Visceral fat areas (VFA) might be clinically important to prevent dementia; however, the association between VFA and cognitive function in the elderly remains unknown. We aimed to evaluate the association between brain structural abnormalities using magnetic resonance imaging (MRI) and VFA, and the association between cognitive function and VFA, in the elderly. A total of 2364 healthy individuals were enrolled, and we excluded those diagnosed with dementia. Participants were divided into a high-VFA and a low-VFA group based on median VFA. The high-VFA group had significantly lower cognitive function than the low-VFA group (p = 0.025), after adjustment for related factors using a linear regression model. Regarding brain structure in MRI, VFA remained significantly associated with white matter lesions (odds ratio (OR), 1.90; 95% confidence interval (1.33–2.70); adjusted p < 0.001) and perivascular space (OR, 1.28; 95% confidence interval (1.02–1.61); adjusted p = 0.033). Further follow-up studies are needed, but reducing visceral fat might be important, not only to prevent cardiovascular disease but also to prevent dementia.

Generalized Muscle Quality Loss as a Risk Factor for Pelvic Organ Prolapse: A Single-Center, Observational Study

Among the physiological changes associated with aging, myopenia due to increased amounts of fatty tissue in muscles and loss of muscle mass have recently gained attention. This study retrospectively examined the relationship between generalized muscle quality and pelvic organ prolapse (POP). Participants comprised 25 patients between 40 and 79 years old showing a Pelvic Organ Prolapse Quantification system stage of 3 or higher who underwent surgery between 2017 and 2019. Control cases comprised 23 patients with benign gynecological diseases who underwent surgery without POP. CT performed within 3 months before surgery was used to measure muscle mass. Smooth muscle index (SMI) was significantly higher in the POP group than in the non-POP group (p = 0.017), and muscle mass was rather large in the POP group. Comparing the POP and non-POP groups, both subcutaneous and visceral fat accumulation were significantly higher in the POP group (p = 0.03, p = 0.002 respectively). Conversely, intramuscular adipose tissue content (IMAC), indicating lower muscle quality, was significantly higher in the POP group (p = 0.024). Multivariate analysis revealed BMI and number of deliveries, but not IMAC, as significant independent risk factors of POP. Although not an independent risk factor, decreased muscle quality was involved in the pathophysiology of POP.