NF-κB-Inducing Kinase Rewires Metabolic Homeostasis and Promotes Diet-Induced Obesity

Obesity is a predominant risk factor for metabolic syndrome, which refers to a cluster of disorders that include diabetes, cardiovascular disease and fatty liver disease. Obesity and overnutrition are associated with aberrant immune and inflammatory responses resulting in increased local fat deposition, insulin resistance and systemic metabolic dysregulation. Here we show NF-κB-inducing kinase (NIK), a critical regulator of immunity and inflammation has local and systemic effects on metabolic processes. We demonstrate that NIK has NF-κB-independent and -dependent roles on adipose development and function. Independently of noncanonical NF- κB, NIK deficiency regulates mitochondrial spare respiratory capacity (SRC) and proton leak but establishes higher basal oxygen consumption and glycolytic capacity in preadipocytes and ex vivo adipose tissue. In addition, we demonstrate NIK promotes adipogenesis through its role in activation of the noncanonical NF-κB pathway. Strikingly, when challenged with a high fat diet, NIK deficient mice are protected against diet-induced obesity and insulin insensitivity. Overall, mice lacking NIK exhibit decreased overall fat mass and increased energy expenditure. Our results establish that, through its influences on adipose development, metabolic homeostasis and rewiring, NIK is a driver of pathologies associated with metabolic dysfunction.

Role of miR-181c in Diet-Induced Obesity Through Regulation of Lipid Synthesis in Liver

We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene (mt-COX1), and influence obesity-induced cardiac dysfunction through mitochondrial pathway. Liver plays a pivotal role during obesity. Therefore, we hypothesized that miR-181c plays an important role in pathophysiological complications associated with obesity. We used miR-181c/d -/- mice to study the miR-181c role in lipogenesis in hepatocytes during diet-induced obesity (DIO). Indirect calorimetric measurements were made during the 26 weeks high fat diet (HFD) exposure. qPCR was performed to examine the gene expression involved in lipid synthesis. Here, we show that miR-181c/d -/- mice are not protected against all metabolic consequences of HFD exposure. After 26 weeks of the HFD, miR-181c/d -/- mice had a significantly higher body fat (%) compared to WT. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d -/- mice. HFD-fed miR-181c/d -/- mice had higher serum and liver triglyceride levels compared to HFD-fed WT mice. qPCR data demonstrated that several genes which are regulated by isocitrate dehydrogenase 1 (IDH1) were upregulated in miR-181c/d -/- liver compared to WT liver. Furthermore, an AAV-8 was used to deliver miR-181c, in vivo , to validate the potential role of miR-181c in the liver. miR-181c delivery attenuate the lipogenesis by downregulating the same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders.

Diabetic Neuropathy: Review on Molecular Mechanisms

: Diabetic mellitus is a worldwide endocrine and metabolic disorder with insulin insensitivity or deficiency or both whose prevalence could rise up to 592 million by 2035. Consistent hyperglycemia leads to one of the most common comorbidities like Diabetic Peripheral Neuropathy (DPN). DPN is underlined with unpleasant sensory experience such as tingling and burning sensation, hyperalgesia, numbness etc. Globally, 50-60% of the diabetic population is suffering from such symptoms like microvascular complication. Consistent hyperglycemia during DM causes activation/inhibition of various pathways playing important role in homeostasis of neurons and other cells. Disruption of these pathways results into apoptosis and mitochondrial dysfunctions causing neuropathy. Among these pathways, pathways like Polyol pathway and PARP pathway are some of the most intensively studied pathways whereas pathways like Wnt pathway, Mitogen activated protein kinase (MAPK), mTOR pathway are comparatively newly discovered. Understanding of these pathways and their role in pathophysiology of DN underlines a few molecules of immense therapeutic value. The inhibitors or activators of these molecules can be of therapeutic importance in management of DPN. This review hence, focuses on these underlying molecular mechanisms intending to provide therapeutically effective molecular targets for treatment of DPN.

The association of insulinemic potential of diet and lifestyle with the risk of insulin-related disorders: a prospective cohort study among participants of Tehran Lipid and Glucose Study

Background We aim to assess the association of empirical dietary (EDIH) and lifestyle (ELIH) index for hyperinsulinemia with the risk of insulin resistance, hyperinsulinemia, insulin sensitivity, and β-cell dysfunction in Iranian adults. Methods In this prospective study, a total of 1244 men and women aged ≥ 20 years were selected among participants of the Tehran lipid and glucose study and followed for 3.2 years. Dietary intakes were assessed using a valid semi-quantitative food frequency questionnaire. Dietary and lifestyle insulinemic potential indices were calculated using dietary intake, body mass index, and physical activity information. Multivariable logistic regression was used to estimate the associated risk of a 3-year incidence of insulin-related disorders. Results The mean ± SD age and BMI of all eligible participants (42.7% males) were 43.0 ± 13.0 and 27.4 ± 4.9 in the study's baseline. After adjusting for all potential confounders, participants in the highest tertile of ELIH score had a greater risk of developing hyperinsulinemia (OR:2.42, 95%CI:1.52–3.86, P for trend = < 0.001), insulin resistance (OR:2.71, 95%CI:1.75–4.18, P for trend = < 0.001) and insulin insensitivity (OR:2.65, 95%CI: 1.72–4.10, P for trend = < 0.001) compared with those in the lowest tertile. However, the risk of incident β-cell dysfunction was lower in individuals with a higher score of ELIH in comparison to those with the lowest score (OR:0.30, 95%CI:0.19–0.45, P for trend = < 0.001). Conclusions Empirical lifestyle index for hyperinsulinemia was directly associated with insulin resistance, insulin insensitivity, and hyperinsulinemia and was inversely associated with β-cells dysfunction.

P0997BLUEBERRY JUICE IMPROVED THE METABOLIC PROFILE IN A PREDIABETIC RAT MODEL INDUCED BY A HYPERCALORIC DIET WITHOUT RENOPROTECTION

Background and Aims Blueberries (BB), due to their enriched content in polyphenolics and in other compounds with potential cytoprotective properties, have been associated with beneficial effects in distinct cardiometabolic conditions. The goal of this study was to evaluate the metabolic and renal effects of long-term blueberry juice (BJ) treatment in a rat model of prediabetes induced by a hypercaloric diet. Method Prediabetes was developed in adult male Wistar rats through the ingestion of high-sucrose (35% HSu) and high-fat (60% HF) diets during 23 wks (HSuHF animals, n=16). After 9 weeks, half of the former rats received BJ orally (25g/kg BW, HSuHF+BJ group). Control animals (n=8) received standard diet during the entire protocol. Glycemic, lipidic and insulinemic profiles were evaluated throughout the protocol, as well as gut microbiota composition, gut barrier permeability, endotoxemia (LPS) and inflammation (hs-CRP). Renal function was assessed by using serum and urinary measures of creatinine, uric acid and blood urea nitrogen and calculating the glomerular filtration rate (GFR). Histological characterization of the kidney was performed by H&E and lipid deposition by Oil Red O staining and quantification of triglycerides. Serum and renal tissue inflammatory markers were evaluated by Elisa (hs-CRP) and by RT-qPCR and/or WB (IL-6, TNF-α, iNOS, MMP2, TLR-4 and RAGE). The study was approved by the local animal welfare body (Ref: 9-2018). Values are presented as means ± S.E.M. and possible differences evaluated by ANOVA/post-hoc tests. Results While no major changes between groups were found for gut microbiota, gut barrier and endotoxemia/inflammation, BJ treatment was able to ameliorate hypercaloric diet-induced glucose intolerance, insulin insensitivity and plasma hypertriglyceridemia. In addition, in the HSuHF+BJ rats there was a trend to alleviate the reduction of GFR found in the HSuHF animals, as well as some early glomerular lesions, including mesangial expansion and basal membrane thickening. However, this nutraceutical intervention was unable to halt or slow down glomerular crescent-like lesions, renal lipidosis and the overexpression of renal IL-6 found in the HSuHF-treated animals. Conclusion Despite the metabolic improvement viewed by the amelioration of glucose intolerance, insulin insensitivity and hypertriglyceridemia, in this rat model of prediabetes a nutraceutical intervention with BJ presented very modest renoprotective effects. Acknowledgements: FEDER, COMPETE and FCT (CENTRO-01-0145-FEDER-000012-HealthyAging2020, UID/NEU/04539/2013, UID/NEU/04539/2019, POCI-01-0145-FEDER-007440, POCI-01-0145-FEDER-031712, PTDC/SAU-NUT/31712/2017 and SFRH/BD/109017/2015), as well as COAPE and MIRTILUSA.

Microbial Reconstitution Reverses Early Female Puberty Induced by Maternal High-fat Diet During Lactation

Recent work shows that gut microbial dysbiosis contributes to the risk of obesity in children whose mothers consume a high-fat diet (HFD) during both gestation and lactation or during gestation alone. Obesity predisposes children to developing precocious puberty. However, to date, no study has examined how maternal HFD (MHFD) during lactation regulates the gut microbiota (GM), pubertal timing, and fertility of offspring. Here, we found that MHFD during lactation markedly altered the GM of offspring. The pups developed juvenile obesity, early puberty, irregular estrous cycles, and signs of disrupted glucose metabolism. Remarkably, permitting coprophagia between MHFD and maternal normal chow offspring successfully reversed the GM changes as well as early puberty and insulin insensitivity. Our data suggest that microbial reconstitution may prevent or treat early puberty associated with insulin resistance.

Ablation of tanycytes of the arcuate nucleus and median eminence increases visceral adiposity and decreases insulin sensitivity in male mice

Tanycytes are radial glial cells located in the mediobasal hypothalamus. Recent studies have proposed that tanycytes play an important role in hypothalamic control of energy homeostasis, although this has not been directly tested. Here, we report the phenotype of mice in which tanycytes of the arcuate nucleus and median eminence were conditionally ablated. Although the CSF-hypothalamic barrier was rendered more permeable, the blood-hypothalamic barrier was not altered. The metabolic effects of tanycyte ablation were likewise moderate. However, we consistently observed a significant increase in visceral fat distribution accompanying insulin insensitivity, but only in male mice, and without an effect on either body weight or food intake. A high-fat diet accelerated overall body weight gain in tanycyte-ablated mice, but the development of visceral adiposity and insulin insensitivity was attenuated. These results clarify the extent to which tanycytes regulate energy metabolism, and indicate a role for tanycytes in controlling body adiposity.

Insulin-insensitivity of male genitalia maintains reproductive success in Drosophila

For most arthropod species, male genital size is relatively implastic in response to variation in developmental nutrition, such that the genitals in large well-fed males are similar in size to those in small poorly-fed males. In Drosophila melanogaster, reduced nutritional plasticity of the male genitalia is a consequence of low insulin sensitivity through a tissue-specific reduction in the expression of FOXO , a negative growth regulator . Despite an understanding of the proximate developmental mechanisms regulating organ size, the ultimate evolutionary mechanisms that may have led to reduced FOXO expression in the genitalia have not been fully elucidated. Here we show that restoring FOXO activity in the developing genitalia reduces the male genital size and decreases various aspects of male reproductive success. These data support the hypothesis that sexual selection has acted on the male genitalia to limit their nutritional plasticity through a reduction in FOXO expression, linking proximate with ultimate mechanisms of genital evolution.