Fish Oil Improves Offspring Metabolic Health of Paternal Obese Mice by Targeting Adipose Tissue.

Obesity is a fast-growing epidemic affecting more than 40% of the US population and leads to co-morbidities such as type 2 diabetes and cancer. More importantly, there is a rapid increase in childhood obesity associated with obesity in parents. Further, offspring are encoded with approximately half of their genetic information from the paternal side. Obesity in fathers at the preconceptional period likely influences the intergenerational development of obesity. This study focuses on the role of fish oil supplementation as a non-pharmacological intervention in fathers and its impact on childhood obesity using animal models. Male mice were fed a low-fat diet or high-fat diet with or without fish oil for 10 weeks and mated with female mice on a chow diet. Offspring were then continued on a chow diet until 8 or 16 weeks. In vivo insulin tolerance was tested to assess the metabolic health of offspring. Further, adipose tissue was harvested upon sacrifice, and genetic markers of inflammation and lipid metabolism in the tissue were analyzed. Offspring of males supplemented with fish oil showed lower body weight, improved insulin tolerance, and altered inflammatory markers. Markers of fatty acid oxidation were higher, while markers of fatty acid synthesis were lower in offspring of fathers fed fish oil. This supports fish oil as an accessible intervention to improve offspring metabolic health.

Enhanced Metabolic Effects of Fish Oil When Combined with Vitamin D in Diet-Induced Obese Male Mice.

Vitamin D (vit D) and fish oil (FO) both offer unique health benefits, however, their combined effects have not been evaluated in obesity and nonalcoholic fatty liver disease (NAFLD). Hence, we hypothesized that vit D and FO supplementation would have additive effects in reducing obesity-associated inflammation and NAFLD. Male C57BL6 mice were split into four groups and fed a high fat (HF) diet supplemented with a low (HF; +200 IU vit D) or high dose of vitamin D (HF + D; +1000 IU vit D); combination of vit D and FO (HF-FO; +1000 IU vit D); or only FO (HF-FO; +200 IU vit D) for 12 weeks. We measured body weight, food intake, glucose tolerance, and harvested epididymal fat pad and liver for gene expression analyses. Adiposity was reduced in groups supplemented with both FO and vit D. Glucose clearance was higher in FO-supplemented groups compared to mice fed HF. In adipose tissue, markers of fatty acid synthesis and oxidation were comparable in groups that received vit D and FO individually in comparison to HF. However, the vit D and FO group had significantly lower fatty acid synthesis and higher oxidation compared to the other groups. Vit D and FO also significantly improved fatty acid oxidation, despite similar fatty acid synthesis among the four groups in liver. Even though we did not find additive effects of vit D and FO, our data provide evidence that FO reduces markers of obesity in the presence of adequate levels of vit D.

Impact of long-term dietary high fat and eicosapentaenoic acid on behavior and hypothalamic-pituitary-adrenal axis activity in amyloidogenic APPswe/PSEN1dE9 mice.

INTRODUCTION: Alzheimer's disease (AD) alters neurocognitive and emotional function and causes dysregulation of multiple homeostatic processes. The leading AD framework pins amyloid beta plaques and tau tangles as primary drivers of dysfunction. However, many additional variables, including diet, stress, sex, age, and pain tolerance, interact in ways that are not fully understood to impact the onset and progression of AD pathophysiology. We asked: 1) does high-fat diet, compared to low-fat diet, exacerbate AD pathophysiology and behavioral decline? And, 2) can supplementation with eicosapentaenoic (EPA)-enriched fish oil prevent high-fat-diet-induced changes? METHODS: Male and female APPswePSdE9 mice, and their non-transgenic littermates, were randomly assigned to a diet condition (low-fat, high-fat, high-fat with EPA) and followed from 2 to 10 months of age. We assessed baseline corticosterone concentration during aging, pain tolerance, cognitive function, stress coping, and corticosterone response to a stressor. RESULTS: Transgenic mice were consistently more active than non-transgenic mice, but did not perform worse on either cognitive task, even though we recently reported that these same transgenic mice exhibited metabolic changes and had increased amyloid beta. Mice fed high-fat diet had higher baseline and post-stressor corticosterone, but diet did not impact cognition or pain tolerance. Sex had the biggest influence, as female mice were consistently more active and had higher corticosterone than males. CONCLUSION: Overall, diet, genotype, and sex did not have consistent impacts on outcomes. We found little support for predicted interactions and correlations, suggesting diet impacts metabolic function and amyloid beta levels, but these outcomes do not translate to changes in behaviors measured here.

Role of Fish Oil in Preventing Paternal Obesity and Improving Offspring Skeletal Muscle Health.

This study investigates the effects of fish oil supplementation during the periconceptional period in male mice. Specifically, it examines the impact of fish oil on intergenerational health, as determined by skeletal muscle markers. To mimic paternal obesity, thirty mice were separated into three groups with distinct dietary regimes for 10 weeks: a high-fat diet (HF), a high-fat diet supplemented with fish oil (FO), and a low-fat diet (LF). Then, these mice mated with control female mice. Dams and offspring consumed a chow diet during gestation and lactation, and the offspring continued on a chow diet. To study short-term (8 weeks) and long-term (16 weeks) effects of FO, skeletal muscle was isolated at the time of sacrifice, and gene analyses were performed. Results suggest that offspring born to FO-supplemented sires exhibited a significant, short-term upregulation of genes associated with insulin signaling, fatty acid oxidation, and skeletal muscle growth with significant downregulation of genes involved in fatty acid synthesis at 8 weeks. Prominent differences in the above markers were observed at 8 weeks compared to 16 weeks. These findings suggest the potential benefits of FO supplementation for fathers during the periconceptional period in reducing the health risks of offspring due to paternal obesity.

Effects of Fish Oil Supplementation on Reducing the Effects of Paternal Obesity and Preventing Fatty Liver in Offspring.

Nonalcoholic fatty liver disease (NAFLD) is a serious public health concern, which calls for appropriate diet/nutrition intervention. Fish oil (FO) has several benefits in reducing obesity, but its intergenerational role in reducing the effects of paternal obesity has not been established. Hence, we hypothesized that FO supplementation to an obese father during the pre-conceptional period could improve the metabolic health of the offspring, specifically in the liver. Three groups of male mice were fed with a low-fat (LF), high-fat (HF), or high-fat diet supplemented with FO (HF-FO) for 10 weeks and were then allowed to mate with female mice fed a chow diet. Offspring were sacrificed at 16 weeks. The liver tissue was harvested for genomic and histological analyses. The offspring of HF and HF-FO fathers were heavier compared to that of the LF mice during 9-16 weeks. The glucose tolerance of the offspring of HF-FO fathers were significantly improved as compared to the offspring of HF fathers. Paternal FO supplementation significantly lowered inflammation and fatty acid synthesis biomarkers and increased fatty acid oxidation biomarkers in the offspring liver. In summary, FO supplementation in fathers shows the potential to reduce metabolic and cardiovascular diseases through genetic means in offspring.

Temperature-Dependent Effects of Eicosapentaenoic Acid (EPA) on Browning of Subcutaneous Adipose Tissue in UCP1 Knockout Male Mice.

Uncoupling protein 1 (UCP1) plays a central role in thermogenic tissues by uncoupling cellular respiration to dissipate energy. Beige adipocytes, an inducible form of thermogenic cells in subcutaneous adipose tissue (SAT), have become a major focus in obesity research. We have previously shown that eicosapentaenoic acid (EPA) ameliorated high-fat diet (HFD)-induced obesity by activating brown fat in C57BL/6J (B6) mice at thermoneutrality (30 °C), independently of UCP1. Here, we investigated whether ambient temperature (22 °C) impacts EPA effects on SAT browning in wild-type (WT) and UCP1 knockout (KO) male mice and dissected underlying mechanisms using a cell model. We observed resistance to diet-induced obesity in UCP1 KO mice fed HFD at ambient temperature, with significantly higher expression of UCP1-independent thermogenic markers, compared to WT mice. These markers included the fibroblast growth factor 21 (FGF21) and sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b), suggesting the indispensable role of temperature in beige fat reprogramming. Surprisingly, although EPA induced thermogenic effects in SAT-derived adipocytes harvested from both KO and WT mice, EPA only increased thermogenic gene and protein expression in the SAT of UCP1 KO mice housed at ambient temperature. Collectively, our findings indicate that the thermogenic effects of EPA, which are independent of UCP1, occur in a temperature-dependent manner.

Eicosapentaenoic Acid Protects against Metabolic Impairments in the APPswe/PS1dE9 Alzheimer's Disease Mouse Model.

BACKGROUND: Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by amyloid-ß (Aß) plaques. Systemic inflammation and obesity may exacerbate AD pathogenesis. We previously reported anti-inflammatory and anti-obesity effects of EPA in mice. OBJECTIVES: We aimed to determine whether EPA reduces obesity-associated metabolic dysfunctions and Aß accumulation in AD amyloidogenic mice. METHODS: Two-mo-old APPswe/PS1dE9 transgenic (TG) mice and non-TG littermates were randomly assigned to low fat (LF; 10% kcal fat), high fat (HF; 45% kcal fat), or EPA (36 g/kg)-supplemented HF diets. Body composition, glucose tolerance, and energy expenditure were measured, and serum and brain metabolic markers were tested 38 wk postintervention. Outcomes were statistically analyzed via 3-factor ANOVA, modeling genotype, sex, and diet interactions. RESULTS: HF-fed males gained more weight than females (Δ = 61 mg; P < 0.001). Compared with LF, HF increased body weights of wild-type (WT) males (Δ = 31 mg; P < 0.001). EPA reduced HF-induced weight gain in WT males (Δ = 24 mg; P = 0.054) but not in females. HF mice showed decreased glucose clearance and respiratory energy compared with LF-fed groups (Δ = -1.31 g/dL; P < 0.001), with no significant effects of EPA. However, EPA conferred metabolic improvements by decreasing serum leptin and insulin (Δ = -2.51 g/mL and Δ = -0.694 ng/mL, respectively compared with HF, P ≤ 0.05) and increasing adiponectin (Δ = 21.6 ng/mL; P < 0.001). As we expected, TG mice expressed higher serum and brain Aß than WT mice (Δ = 0.131 ng/mL; P < 0.001 and Δ = 0.56%; P < 0.01, respectively), and EPA reduced serum Aß1-40 in TG males compared with HF (Δ = 0.053 ng/mL; P ≤ 0.05). CONCLUSIONS: To our knowledge, this is the first report that EPA reduces serum Aß1-40 in obese AD male mice, warranting further investigations into tissue-specific mechanisms of EPA in AD.

Effect of Dietary Geranylgeraniol and Green Tea Polyphenols on Glucose Homeostasis, Bone Turnover Biomarkers, and Bone Microstructure in Obese Mice.

Previously, we demonstrated that the administration of either geranylgeraniol (GGOH) or green tea polyphenols (GTP) improved bone health. This study examined the combined effects of GGOH and GTP on glucose homeostasis in addition to bone remodeling in obese mice. We hypothesized that GGOH and GTP would have an additive or synergistic effect on improving glucose homeostasis and bone remodeling possibly in part via suppression of proinflammatory cytokines. Forty-eight male C57BL/6J mice were assigned to a high-fat diet (control), HFD + 400 mg GGOH/kg diet (GG), HFD + 0.5% GTP water (TP), or HFD + GGOH + GTP (GGTP) diet for 14 weeks. Results demonstrated that GTP supplementation improved glucose tolerance in obese mice. Neither GGOH nor GTP affected pancreas insulin or bone formation procollagen type I intact N-terminal, bone volume at the lumbar vertebrae, or bone parameters at the trabecular bone and cortical bone of the femur. There was an interactive effect for serum bone resorption collagen type 1 cross-linked C-telopeptide concentrations, resulting in no-GGOH and no-GTP groups having the highest values. GGOH increased trabecular number and decreased trabecular separation at the lumbar vertebrae. GTP increased trabecular thickness at lumbar vertebrae. The GG group produced the greatest connectivity density and the lowest structure model index. Only GTP, not GGOH, decreased adipokines concentrations (resistin, leptin, monocyte chemoattractant protein-1, and interleukin-6). In an obese male mouse model, individual GGOH and GTP supplementation improved glucose homeostasis, serum CTX, and trabecular microstructure of LV-4. However, the combined GGOH and GTP supplementation compromises such osteoprotective effects on serum CTX and trabecular bone of obese mice.

Anti-inflammatory mechanisms of polyphenols in adipose tissue: role of gut microbiota, intestinal barrier integrity and zinc homeostasis.

Obesity is associated with an imbalance of micro-and macro-nutrients, gut dysbiosis, and a "leaky" gut phenomenon. Polyphenols, such as curcumin, resveratrol, and anthocyanins may alleviate the systemic effects of obesity, potentially by improving gut microbiota, intestinal barrier integrity (IBI), and zinc homeostasis. The essential micronutrient zinc plays a crucial role in the regulation of enzymatic processes, including inflammation, maintenance of the microbial ecology, and intestinal barrier integrity. In this review, we focus on IBI- which prevents intestinal lipopolysaccharide (LPS) leakage - as a critical player in polyphenol-mediated protective effects against obesity-associated white adipose tissue (WAT) inflammation. This occurs through mechanisms that block the movement of the bacterial endotoxin LPS across the gut barrier. Available research suggests that polyphenols reduce WAT and systemic inflammation via crosstalk with inflammatory NF-κB, the mammalian target of rapamycin (mTOR) signaling and zinc homeostasis.

Long-term effects of adolescent exposure to olanzapine in C57BL/6 J mice and the impact of dietary fish oil supplementation.

RATIONALE: Second-generation antipsychotic (SGA) medications can produce abnormal weight gain and metabolic dysfunction in children, but little is known about the post-treatment consequences of adolescent SGA exposure. OBJECTIVES: The objective of this study was to determine the long-term, post-treatment effects of adolescent olanzapine exposure on weight and metabolic function and whether dietary fish oil (FO) modulated any observed effects of olanzapine. METHODS: Male and female mice were fed a high-fat, high-sugar (HF-HS) diet or an HF-HS diet supplemented with fish oil (HF-HS-FO) and were treated with olanzapine or vehicle for 29 days beginning on postnatal day 37. RESULTS: In male mice, adolescent olanzapine treatment suppressed weight gain during and after treatment and improved metabolic function in adulthood; dietary fish oil reduced weight gain, increased expression of fatty acid oxidation genes, and decreased expression of genes associated with fatty acid synthesis and inflammation. In contrast, few effects were observed in female mice. CONCLUSIONS: The current results suggest that adolescent olanzapine exposure can produce long-term alterations in weight and metabolic function in male mice and that dietary fish oil can reduce adverse effects of lifelong consumption of an HF-HS diet. Because expected adverse effects of adolescent olanzapine treatment were not observed, the potential beneficial effects of dietary fish oil for SGA-induced weight gain and metabolic dysfunction could not be evaluated.

Effects of captopril on glucose metabolism and autophagy in liver and muscle from mice with type 1 diabetes and diet-induced obesity.

Impaired metabolic functions underlie the pathophysiology of diabetes and obesity. The renin-angiotensin system (RAS) is one pathway related to the pathophysiology of both diseases. RAS activation in metabolically active tissues exerts pro-inflammatory effects via angiotensin II (Ang II), linked to dysfunction in cellular processes such as autophagy, which is associated with obesity and diabetes. Here, we determined whether RAS is involved in metabolic dysregulations in a Type 1 Diabetes (T1D) mouse model, treated with captopril, and in an obesity mouse model (Agt-Tg) that overexpresses angiotensinogen (Agt) in adipose tissue. T1D mice had lower plasma leptin, resistin and higher non-esterified fatty acids (NEFA) compared to wild type (Wt) mice, even under captopril treatment. Further, mRNA levels for Agt, At1, Insr, and Beclin1 were upregulated in muscle and liver of T1D mice with captopril compared to Wt. Moreover, autophagy markers LC3 and p62 proteins were decreased, regardless of captopril treatment in the liver from T1D mice. In obese Wt mice, captopril increased muscle Irs1 gene levels. Further, captopril reduced mRNA levels of At1, Insr, Ampk, Beclin1, Atg12, and Lc3 in the liver from both Wt and Agt-Tg mice, while Agt, At1, Insr, and Atg12 expression was reduced in Agt-Tg mice without captopril treatment. Irs1 expression was decreased in the liver from obese Wt mice treated with captopril. Our results suggest that captopril treatment upregulates components of RAS, insulin signaling, and autophagy in both muscle and liver, indicating potential utility of captopril in targeting both insulin sensitivity and autophagy in diabetes and obesity.

Engineering and Characterization of a Biomimetic Microchip for Differentiating Mouse Adipocytes in a 3D Microenvironment.

Although two-dimensional (2D) cell cultures are the standard in cell research, one pivotal disadvantage is the lack of cell-cell and cell-extracellular matrix (ECM) signaling in the culture milieu. However, such signals occur in three-dimensional (3D) in vivo environments and are essential for cell differentiation, proliferation, and a range of cellular functions. In this study, we developed a microfluidic device to proliferate and differentiate functional adipose tissue and adipocytes by utilizing 3D cell culture technology. This device was used to generate a tissue-specific 3D microenvironment to differentiate 3T3-L1 preadipocytes into either visceral white adipocytes using visceral adipose tissue (VAT) or subcutaneous white adipose tissue (SAT). The microchip has been tested and validated by functional assessments including cell morphology, inflammatory response to a lipopolysaccharide (LPS) challenge, GLUT4 tracking, and gene expression analyses. The biomimetic microfluidic chip is expected to mimic functional adipose tissues that can replace 2D cell cultures and allow for more accurate analysis of adipose tissue physiology.

Sex Differences in Fish Oil and Olanzapine Effects on Gut Microbiota in Diet-Induced Obese Mice.

Children are prescribed second-generation antipsychotic (SGA) medications, such as olanzapine (OLZ) for FDA-approved and "off-label" indications. The long-term impact of early-life SGA medication exposure is unclear. Olanzapine and other SGA medications are known to cause excessive weight gain in young and adult patients, suggesting the possibility of long-term complications associated with the use of these drugs, such as obesity, diabetes, and heart disease. Further, the weight gain effects of OLZ have previously been shown to depend on the presence of gut bacteria and treatment with OLZ, which shifts gut bacteria toward an "obesogenic" profile. The purpose of the current study was to evaluate changes in gut bacteria in adult mice following early life treatment with OLZ and being fed either a high-fat diet or a high-fat diet supplemented with fish oil, which has previously been shown to counteract gut dysbiosis, weight gain, and inflammation produced by a high-fat diet. Female and male C57Bl/6J mice were fed a high fat diet without (HF) or with the supplementation of fish oil (HF-FO) and treated with OLZ from postnatal day (PND) 37-65 resulting in four groups of mice: mice fed a HF diet and treated with OLZ (HF-OLZ), mice fed a HF diet and treated with vehicle (HF), mice fed a HF-FO diet and treated with OLZ (HF-FO-OLZ), and mice fed a HF-FO diet and treated with vehicle (HF-FO). Following euthanasia at approximately 164 days of age, we determined changes in gut bacteria populations and serum LPS binding protein, an established marker of gut inflammation and dysbiosis. Our results showed that male HF-FO and HF-FO-OLZ mice had lower body weights, at sacrifice, compared to the HF group, with a comparable body weight across groups in female mice. HF-FO and HF-FO-OLZ male groups also exhibited lower serum LPS binding protein levels compared to the HF group, with no differences across groups in female mice. Gut microbiota profiles were also different among the four groups; the Bacteroidetes-to-Firmicutes (B/F) ratio had the lowest value of 0.51 in the HF group compared to 0.6 in HF-OLZ, 0.9 in HF-FO, and 1.1 in HF-FO-OLZ, with no differences in female mice. In conclusion, FO reduced dietary obesity and its associated inflammation and increased the B/F ratio in male mice but did not benefit the female mice. Although the weight lowering effects of OLZ were unexpected, FO effects persisted in the presence of olanzapine, demonstrating its potential protective effects in male subjects using antipsychotic drugs.

Sex-Dependent Effects of Eicosapentaenoic Acid on Hepatic Steatosis in UCP1 Knockout Mice.

Visceral obesity may be a driving factor in nonalcoholic fatty liver disease (NAFLD) development. Previous studies have shown that the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA), ameliorates obesity in high-fat (HF) fed male, C57Bl/6 mice at thermoneutral conditions, independent of uncoupling protein 1 (UCP1). Our goals herein were to investigate sex-dependent mechanisms of EPA in the livers of wild type (WT) and UCP1 knockout (KO) male and female mice fed a HF diet (45% kcal fat; WT-HF, KO-HF) with or without supplementation of 36 g/kg EPA (WT-EPA, KO-EPA). KO significantly increased body weight in males, with no significant reductions with EPA in the WT or KO groups. In females, there were no significant differences in body weight among KO groups and no effects of EPA. In males, liver TGs were significantly higher in the KO-HF group and reduced with EPA, which was not observed in females. Accordingly, gene and protein markers of mitochondrial oxidation, peroxisomal biogenesis and oxidation, as well as metabolic futile cycles were sex-dependently impacted by KO and EPA supplementation. These findings suggest a genotypic difference in response to dietary EPA supplementation on the livers of male and female mice with diet-induced obesity and housed at thermoneutrality.

Sex Differences in Early Programming by Maternal High Fat Diet Induced-Obesity and Fish Oil Supplementation in Mice.

Pre-pregnancy obesity is a contributing factor for impairments in offspring metabolic health. Interventional strategies during pregnancy are a potential approach to alleviate and/or prevent obesity and obesity related metabolic alterations in the offspring. Fish oil (FO), rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) exerts metabolic health benefits. However, the role of FO in early life remains still unknown. Hence, this study objective was to determine the effect of FO supplementation in mice from pre-pregnancy through lactation, and to study the post-natal metabolic health effects in gonadal fat and liver of offspring fed high fat (HF) diet with or without FO. Female C57BL6J mice aged 4-5 weeks were fed a HF (45% fat) diet supplemented with or without FO (30 g/kg of diet) and low fat (LF; 10% fat) pre-pregnancy through lactation. After weaning, offspring (male and female) from HF or FO dams either continued the same diet (HF-HF and FO-FO) or switched to the other diet (HF-FO and FO-HF) for 13 weeks, creating four groups of treatment, and LF-LF was used as a control group. Serum, gonadal fat and liver tissue were collected at termination for metabolic analyses. Offspring of both sexes fed HF with or without fish oil gained (p < 0.05) more weight post weaning, compared to LF-LF-fed mice. All the female offspring groups supplemented with FO had reduced body weight compared to the respective male groups. Further, FO-FO supplementation in both sexes (p < 0.05) improved glucose clearance and insulin sensitivity compared to HF-HF. All FO-FO fed mice had significantly reduced adipocyte size compared to HF-HF group in both male and females. Inflammation, measured by mRNA levels of monocyte chemoattractant protein 1 (Mcp1), was reduced (p < 0.05) with FO supplementation in both sexes in gonadal fat and in the liver. Markers of fatty acid synthesis, fatty acid synthase (Fasn) showed no sex specific differences in gonadal fat and liver of mice supplemented with HF. Female mice had lower liver triglycerides than male counterparts. Supplementation of FO in mice improved metabolic health of offspring by lowering markers of lipid synthesis and inflammation.

Curcumin Reduces Adipose Tissue Inflammation and Alters Gut Microbiota in Diet-Induced Obese Male Mice.

SCOPE: Obesity prevalence continues to increase and contribute to metabolic diseases, potentially by driving systemic inflammation. Curcumin is an anti-inflammatory spice with claimed health benefits. However, mechanisms by which curcumin may reduce obesity-associated inflammation are poorly understood; thus, it is hypothesized that benefits of curcumin consumption may occur through reduced white adipose tissue (WAT) inflammation and/or beneficial changes in gut bacteria. METHODS AND RESULTS: Male B6 mice are fed high-fat diets (HFD, 45% kcal fat) or HFD supplemented with 0.4% (w/w) curcumin (HFC) for 14 weeks. Curcumin supplementation significantly reduces adiposity and total macrophage infiltration in WAT, compared to HFD group, consistent with reduced mRNA levels of M1 (Cd80, Cd38, Cd11c) and M2 (Arginase-1) macrophage markers. Moreover, curcumin supplementation reduces expression of other key pro-inflammatory genes, such as NF-κB p65 subunit (p65), Stat1, Tlr4, and Il6, in WAT (p < 0.05). Using microbial 16S RNA sequencing, it is demonstrated that the relative abundance of the Lactococcus, Parasutterella, and Turicibacter genera are increased in the HFC group versus HFD. CONCLUSIONS: Curcumin exerts protective metabolic effects in dietary obesity, in part through downregulation of adipose tissue inflammation, which may be mediated by alterations in composition of gut microbiota, and metabolism of curcumin into curcumin-O-glucuronide.

Maternal Obesity: A Focus on Maternal Interventions to Improve Health of Offspring.

Maternal obesity has many implications for offspring health that persist throughout their lifespan that include obesity and cardiovascular complications. Several different factors contribute to obesity and they encompass interplay between genetics and environment. In the prenatal period, untreated obesity establishes a foundation for a myriad of symptoms and negative delivery experiences, including gestational hypertensive disorders, gestational diabetes, macrosomia, and labor complications. However, data across human and animal studies show promise that nutritional interventions and physical activity may rescue much of the adverse effects of obesity on offspring metabolic health. Further, these maternal interventions improve the health of the offspring by reducing weight gain, cardiovascular disorders, and improving glucose tolerance. Mechanisms from animal studies have also been proposed to elucidate the signaling pathways that regulate inflammation, lipid metabolism, and oxidative capacity of the tissue, ultimately providing potential specific courses of treatment. This review aims to pinpoint the risks of maternal obesity and provide plausible intervention strategies. We delve into recent research involving both animal and human studies with maternal interventions. With the increasing concerning of obesity rates witnessed in the United States, it is imperative to acknowledge the long-term effects posed on future generations and specifically modify maternal nutrition and care to mitigate these adverse outcomes.

Uncoupling protein 1-independent effects of eicosapentaenoic acid in brown adipose tissue of diet-induced obese female mice.

Brown adipose tissue (BAT) plays a key role in energy expenditure through its thermogenic function, making its activation a popular target to reduce obesity. We recently reported that male mice housed at thermoneutrality with uncoupling protein 1 (UCP1) deficiency had increased weight gain and glucose intolerance, but eicosapentaenoic acid (EPA) ameliorated these effects. Whether female mice respond similarly to lack of UCP1 and to EPA remains unknown. We hypothesize that the effects of EPA on BAT activation are independent of UCP1 expression. We used female wild type (WT) and UCP1 knockout (KO) mice housed at thermoneutrality (30°C) as an obesogenic environment and fed them high fat (HF) diets with or without EPA for up to 14 weeks. Body weight (BW), body composition, and insulin and glucose tolerance tests were performed during the feeding trial. At termination, serum and BAT were harvested for further analyses. Mice in the KO-EPA group had significantly lower BW than KO-HF mice. In addition, KO-HF mice displayed significantly impaired glucose tolerance compared to their WT-HF littermates. However, EPA significantly enhanced glucose clearance in the KO mice compared to KO-HF mice. Protein levels of the mitochondrial cytochrome C oxidase subunits I, II, and IV were significantly lower in KO mice compared to WT. Our findings support that ablation of UCP1 is detrimental to energy metabolism of female mice in thermoneutral conditions. However, unexpectedly, EPA's protective effects against diet-induced obesity and glucose intolerance in these mice were independent of UCP1.

Mechanisms linking endoplasmic reticulum (ER) stress and microRNAs to adipose tissue dysfunction in obesity.

Over accumulation of lipids in adipose tissue disrupts metabolic homeostasis by affecting cellular processes. Endoplasmic reticulum (ER) stress is one such process affected by obesity. Biochemical and physiological alterations in adipose tissue due to obesity interfere with adipose ER functions causing ER stress. This is in line with increased irregularities in other cellular processes such as inflammation and autophagy, affecting overall metabolic integrity within adipocytes. Additionally, microRNAs (miRNAs), which can post-transcriptionally regulate genes, are differentially modulated in obesity. A better understanding and identification of such miRNAs could be used as novel therapeutic targets to fight against diseases. In this review, we discuss ways in which ER stress participates as a common molecular process in the pathogenesis of obesity-associated metabolic disorders. Moreover, our review discusses detailed underlying mechanisms through which ER stress and miRNAs contribute to metabolic alteration in adipose tissue in obesity. Hence, identifying mechanistic involvement of miRNAs-ER stress cross-talk in regulating adipose function during obesity could be used as a potential therapeutic approach to combat chronic diseases, including obesity.

C-Peptide as a Therapy for Type 1 Diabetes Mellitus.

Diabetes mellitus (DM) is a complex metabolic disease affecting one-third of the United States population. It is characterized by hyperglycemia, where the hormone insulin is either not produced sufficiently or where there is a resistance to insulin. Patients with Type 1 DM (T1DM), in which the insulin-producing beta cells are destroyed by autoimmune mechanisms, have a significantly increased risk of developing life-threatening cardiovascular complications, even when exogenous insulin is administered. In fact, due to various factors such as limited blood glucose measurements and timing of insulin administration, only 37% of T1DM adults achieve normoglycemia. Furthermore, T1DM patients do not produce C-peptide, a cleavage product from insulin processing. C-peptide has potential therapeutic effects in vitro and in vivo on many complications of T1DM, such as peripheral neuropathy, atherosclerosis, and inflammation. Thus, delivery of C-peptide in conjunction with insulin through a pump, pancreatic islet transplantation, or genetically engineered Sertoli cells (an immune privileged cell type) may ameliorate many of the cardiovascular and vascular complications afflicting T1DM patients.