Rodent Models Of Obesity Research Articles

Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview.

The incidence of metabolic disorders, as well as of neurodegenerative diseases—mainly the sporadic forms of Alzheimer’s and Parkinson’s disease—are increasing worldwide. Notably, obesity, diabetes, and hypercholesterolemia have been indicated as early risk factors for sporadic forms of Alzheimer’s and Parkinson’s disease. These conditions share a range of molecular and cellular features, including protein aggregation, oxidative stress, neuroinflammation, and blood-brain barrier dysfunction, all of which contribute to neuronal death and cognitive impairment. Rodent models of obesity, diabetes, and hypercholesterolemia exhibit all the hallmarks of these degenerative diseases, and represent an interesting approach to the study of the phenotypic features and pathogenic mechanisms of neurodegenerative disorders. We review the main pathological aspects of Alzheimer’s and Parkinson’s disease as summarized in rodent models of obesity, diabetes, and hypercholesterolemia.

The chemokine CXCL14 is negatively associated with obesity and concomitant type-2 diabetes in humans.

Chemokine (C-X-C motif) ligand-14 (CXCL14) levels are downregulated in experimental rodent models of obesity. Moreover, CXCL14 reportedly favors insulin sensitization in obese mice. Here we examined, for the first time, the role of CXCL14 in human obesity. We found that circulating levels of CXCL14 were decreased in patients with obesity and, especially, those with concomitant type-2 diabetes. CXCL14 levels were negatively associated with BMI and with indices of impaired glucose/insulin homeostasis. CXCL14 expression was decreased in subcutaneous adipose tissue from patients with obesity and type-2 diabetes. In adipose tissue, CXCL14 expression was negatively correlated with the expression of genes encoding pro-inflammatory molecules, and positively correlated with GLUT4 and adiponectin expression. In conclusion, obesity, and especially, concomitant type-2 diabetes are associated with abnormally decreased levels of CXCL14 in blood and impaired CXCL14 expression in adipose tissue. CXCL14 downregulation may be a novel biomarker of altered metabolism in obesity. CXCL14 also deserves further research as a therapeutic candidate.

Renal lipid accumulation, oxidative stress and uric acid handling in a rodent model of obesity and metabolic syndrome

Hyperuricemia is more prevalent among people with obesity and metabolic syndrome, and is associated with adverse clinical outcomes. We hypothesized that increased renal reabsorption of uric acid (UA) in obesity...

Changes in bone mass associated with obesity and weight loss in humans: Applicability of animal models.

The implications of obesity and weight loss for human bone health are not well understood. Although the bone changes associated with weight loss are similar in humans and rodents, that is not the case for obesity. In humans, obesity is generally associated with increased bone mass, an outcome which is exacerbated by advanced age and menopause. In rodents, by contrast, bone mass decreases in proportion to severity and duration of obesity, and is influenced by sex, age and mechanical load. Despite these discrepancies, rodents are frequently used to model the situation in humans. In this review, we summarise the existing knowledge of the effects of obesity and weight loss on bone mass in humans and rodents, focusing on the translatability of findings from animal models. We then describe how animal models should be used to broaden the understanding of the relationship between obesity, weight loss, and skeletal health in humans. Specifically, we highlight the aspects of study design that should be considered to optimise translatability of the rodent models of obesity and weight loss. Notably, the sex, age, and nutritional status of the animals should ideally match those of interest in humans. With these caveats in mind, and depending on the research question asked, our review underscores that animal models can provide valuable information for obesity and weight-management research.

Metabolic Responses to Butyrate Supplementation in LF- and HF-Fed Mice Are Cohort-Dependent and Associated with Changes in Composition and Function of the Gut Microbiota

The gut microbiota and associated metabolites have emerged as potential modulators of pathophysiological changes in obesity and related metabolic disorders. Butyrate, a product of bacterial fermentation, has been shown to have beneficial effects in obesity and rodent models of diet-induced obesity. Here, we aimed to determine the beneficial effects of butyrate (as glycerol ester of butyrate monobutyrin, MB) supplementation on metabolic phenotype, intestinal permeability and inflammation, feeding behavior, and the gut microbiota in low-fat (LF)- and high-fat (HF)-fed mice. Two cohorts (separated by 2 weeks) of male C57BL/6J mice (n = 24 in each cohort, 6/group/cohort; 6 weeks old) were separated into four weight-matched groups and fed either a LF (10 % fat/kcal) or HF (45% fat/kcal) with or without supplementation of MB (LF/MB or HF/MB) at 0.25% (w/v) in drinking water for 6 weeks. Metabolic phenotypes (body weight and adiposity), intestinal inflammation, feeding behavior, and fecal microbiome and metabolites were measured. Despite identical genetic and experimental conditions, we found marked differences between cohorts in the response (body weight gain, adiposity, and intestinal permeability) to HF-diet and MB. Notably, the composition of the gut microbiota was significantly different between cohorts, characterized by lower species richness and differential abundance of a large number of taxa, including subtaxa from five phyla, including increased abundance of the genera Bacteroides, Proteobacteria, and Parasutterella in cohort 2 compared to cohort 1. These differences may have contributed to the differential response in intestinal permeability to the HF diet in cohort 2. MB supplementation had no significant effect on metabolic phenotype, but there was a trend to protect from HF-induced impairments in intestinal barrier function in cohort 1 and in sensitivity to cholecystokinin (CCK) in both cohorts. These data support the concept that microbiota composition may have a crucial effect on metabolic responses of a host to dietary interventions and highlight the importance of taking steps to ensure reproducibility in rodent studies.

The probiotic strain h. Alvei ha4597® improves weight loss in overweight subjects under moderate hypocaloric diet: a multicenter randomized, placebo-controlled study

Rationale: Increased evidence supports the role of gut microbiota in the control of body weight. Moreover, recent studies have reported that the probiotic strain HA4597® (HA),which produces the satietogenic peptide ClpB mimicking the effect of alpha-MSH, reduced weight gain and adiposity in rodent models of obesity.

Unacylated ghrelin overexpression improves adipose tissue mitochondrial function and insulin sensistivity and lowers adipocyte expansion markers in obese mice

Rationale: In obese patients, besides absolute fat mass quantity, dysfunctional adipose tissue with fat cell hypertrophy importantly increases metabolic risk including the development of type 2 diabetes. Recent evidence shows that adipocyte expansion both causes and is sustained by disrupted cell metabolism, with reduced mitochondrial function and insulin signaling. The unacylated form of the gastric hormone ghrelin (UnAG) increases skeletal muscle mitochondrial function and insulin signalling in obese rodent models; however, its potential effects on adipose tissue metabolism are currently unknown.

Inorganic nitrite alters mitochondrial dynamics without overt changes in cell death and mitochondrial respiration in cardiomyoblasts under hyperglycemia

Inorganic nitrate or nitrite supplementation has been reported to demonstrate positive outcomes in rodent models of obesity and diabetes as well as in type 2 diabetic humans and even included in clinical trials pertaining to cardiovascular diseases in the recent decade. However, there are contrasting data regarding the useful and toxic effects of the anions. The primary scope of this study was to analyze the beneficial/detrimental alterations in redox status, mitochondrial dynamics and function, and cellular fitness in cardiomyoblasts inflicted by nitrite under hyperglycemic conditions compared with normoglycemia. Nitrite supplementation in H9c2 myoblasts under high glucose diminishes the Bcl-xL expression and mitochondrial ROS levels without significant initiation of cell death or decline in total ROS levels. Concomitantly, there are tendencies towards lowering of mitochondrial membrane potential, but without noteworthy changes in mitochondrial biogenesis and respiration. The study also revealed that under high glucose stress, nitrite may alter mitochondrial dynamics by Drp1 activation possibly via Akt1-Pim1 axis. Moreover, the study revealed differential effects of Drp1 silencing and/or nitrite under the above glycemic conditions. Overall, the study warrants more research regarding the effects of nitrite therapy in cardiac cells exposed to hyperglycemia.

Stapled and Xenopus Glucagon-Like Peptide 1 (GLP-1)-Based Dual GLP-1/Gastrin Receptor Agonists with Improved Metabolic Benefits in Rodent Models of Obesity and Diabetes.

Diabetes is characterized by pancreas dysfunction and is commonly associated with obesity. Hypoglycemic agents capable of improving β-cell function and reducing body weight therefore are gaining increasing interest. Though glucagon-like peptide 1 receptor (GLP-1R)/cholecystokinin 2 receptor (CCK-2R) dual agonist ZP3022 potently increases β-cell mass and improves glycemic control in diabetic db/db mice, the in vivo half-life (t1/2) is short, and its body weight reducing activity is limited. Here, we report the discovery of a series of novel GLP-1R/CCK-2R dual agonists. Starting from Xenopus GLP-1, dual cysteine mutation was conducted followed by covalent side chain stapling and albumin binder incorporation, resulting in a stabilized secondary structure, increased agonist potency, and improved stability. Further C-terminal conjugation of gastrin-6 generated GLP-1R/CCK-2R dual agonists, among which 6a and 6b showed higher stability and hypoglycemic activity than liraglutide and ZP3022. Desirably, 6a and 6b exhibited prominent metabolic benefits in diet-induced obesity mice without causing nausea responses and exerted considerable effects on β-cell restoration in db/db mice. These preclinical studies suggest the potential role of GLP-1R/CCK-2R dual agonists as effective agents for treating diabetes and related metabolic disorders.

Mechanisms Mediating Anti-Inflammatory Effects of Delta-Tocotrienol and Tart Cherry Anthocyanins in 3T3-L1 Adipocytes.

Chronic low-grade inflammation is a primary characteristic of obesity and can lead to other metabolic complications including insulin resistance and type 2 diabetes (T2D). Several anti-inflammatory dietary bioactives decrease inflammation that accompanies metabolic diseases. We are specifically interested in delta-tocotrienol, (DT3) an isomer of vitamin E, and tart cherry anthocyanins (TCA), both of which possess individual anti-inflammatory properties. We have previously demonstrated that DT3 and TCA, individually, reduced systemic and adipose tissue inflammation in rodent models of obesity. However, whether these compounds have combinatorial effects has not been determined yet. Hence, we hypothesize that a combined treatment of DT3 and TCA will have great effects in reducing inflammation in adipocytes, and that these effects are mediated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), a major inflammatory transcription factor. We used 3T3-L1 adipocytes and treated them with 1–5 µM doses of DT3 along with tart cherry containing 18–36 µg anthocyanin/mL, to assess effects on inflammation. Neither DT3 nor TCA, nor their combinations had toxic effects on adipocytes. Furthermore, pro-inflammatory markers interleukin-6 (IL-6) and p-65 (subunit of NFkB) were reduced at the protein level in media collected from adipocytes with both individual and combined treatments. Additionally, other downstream targets of NFkB including macrophage inflammatory protein 2 (Mip2), and Cyclooxygenase-2 (Cox2) were also significantly downregulated (p ≤ 0.05) when treated with individual and combined doses of DT3 and TCA with no additional combinatorial effects. In summary, DT3 and TCA individually, are beneficial in reducing inflammation with no additional combinatorial effects.

Effects of High-Fat Diet at Two Energetic Levels on Fecal Microbiota, Colonic Barrier, and Metabolic Parameters in Dogs.

Increased consumption of energy-rich foods is a key factor in overweight, obesity, and associated metabolic disorders. This would be, at least in part, related to microbiota disturbance. In rodent models of obesity, microbiota disruption has been associated with alteration of the intestinal barrier, endotoxemia, inflammation grade, and insulin sensitivity. The aim of the present study was to assess the effects of a high-fat diet (HFD), fed at two energetic levels, on microbiota, intestinal barrier, and inflammatory and metabolic parameters in dogs. A HFD (33% fat as fed, 4,830 kcal/kg) was given to 24 healthy Beagle dogs at 100% (HF-100; n = 8) and at 150% (HF-150; n = 16) of their maintenance energy requirements for 8 weeks. Analysis of similarity revealed a significant difference in gut microbiota β-diversity following the diet compared to week 0 in both groups while α-diversity was lower only in the HF-150 group. Firmicutes/Bacteroidetes ratio was higher in the HF-150 group compared to the HF-100 group at weeks 2 and 8. A reduction in insulin sensitivity was observed over time in the HF150 group. Neither endotoxemia nor inflammation was observed in either group, did not find supporting data for the hypothesis that the microbiota is involved in the decline of insulin sensitivity through metabolic endotoxemia and low-grade inflammation. Colonic permeability was increased at week 4 in both groups and returned to initial levels at week 8, and was associated with modifications to the expression of genes involved in colonic barrier function. The increase in intestinal permeability may have been caused by the altered intestinal microbiota and increased expression of genes encoding tight junction proteins might indicate a compensatory mechanism to restore normal permeability. Although simultaneous changes to the microbiota, barrier permeability, inflammatory, and metabolic status have not been observed, such a causal link cannot be excluded in dogs overfed on a HFD. Further studies are necessary to better understand the link between HFD, intestinal microbiota and the host.

Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR)

Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic receptors to treat metabolic diseases. Activation of constitutive androstane receptor (CAR), a xenobiotic-sensing nuclear receptor, has been shown to inhibit obesity, suppress hepatic gluconeogenesis, and ameliorate hyperglycemia in rodent models of obesity and type 2 diabetes. However, the underlying molecular mechanism remains to be defined. The growth arrest and DNA damage-inducible gene 45b (Gadd45b), a well-known anti-apoptotic factor, has been shown to be an inducible coactivator of CAR in promoting rapid liver growth. It is unknown whether the effect of CAR on energy metabolism depends on GADD45B. In the present study and by using a high fat diet (HFD)-induced obesity model, we show that reduced body weight gain and improved insulin sensitivity by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) were markedly blunted in Gadd45b knockout mice. Mechanistically, the TCPOBOP-responsive inhibition of hepatic lipogenesis, gluconeogenesis, and adipose inflammation observed in wild type mice were largely abolished in Gadd45b knockout mice. We conclude that Gadd45b is required in part for the metabolic benefits of CAR activation.

Zebrafish shares common metabolic pathways with mammalian olanzapine-induced obesity

BackgroundOlanzapine is one of the most prescribed antipsychotic agents in the pharmacotherapy of psychiatric illness; however, it is associated with multiple side effects primarily obesity. Multiple investigations have been made to model the olanzapine-induced obesity in rodent models which was found to be dose-dependent, gender-dependent, and species-dependent. Danio rerio is a choice of an animal model to understand the pathogenesis of multiple diseases. The present study dealt to understand the olanzapine-associated obesity in zebrafish using in silico and wet-lab experimental protocols by performing gene set enrichment analysis, phylogeny comparison of receptors, and assessing the effect of olanzapine on metabolic rate, lipid metabolism, body weight, and food intake in zebrafish.ResultsThe metabolic pathway was predicted to be majorly modulated by olanzapine in human, rat, mouse, and zebrafish. A clade of receptors of rat, mouse, and human receptor for feeding and satiety center was found similar to zebrafish. The decrease in lipid metabolism was observed in zebrafish larvae if exposed to olanzapine solution. Similarly, there was a significant decrease in metabolic rate in 200 μM and 400 μM concentration of olanzapine.ConclusionEnrichment analysis predicted the probable modulation of metabolic pathways in zebrafish if exposed to olanzapine. Further, olanzapine was identified to play a prime role in decreasing lipid metabolism and metabolic rate and increasing food intake and weight gain in zebrafish which suggests the validation of this model for olanzapine-induced obesity.

Fish oil and corn oil induced differential effect on beiging of visceral and subcutaneous white adipose tissue in high-fat-diet-induced obesity

Obesity is characterised by excessive accumulation of fat in white adipose tissue (WAT) which is compartmentalised into two anatomically and functionally diverse depots - visceral and subcutaneous. Advice to substitute essential polyunsaturated fatty acids (PUFAs) for saturated fatty acids is a cornerstone of various obesity management strategies. Despite an array of reports on the role of essential PUFAs on obesity, there still exists a lacuna on their mode of action in distinct depots i.e. visceral (VWAT) and subcutaneous (SWAT). The present study aimed to evaluate the effect of fish oil and corn oil on VWAT and SWAT in high-fat-diet-induced rodent model of obesity. Fish oil (FO) supplementation positively ameliorated the effects of HFD by regulating the anthropometrical and serum lipid parameters. FO led to an overall reduction in fat mass in both depots while specifically inducing beiging of adipocytes in SWAT as indicated by increased UCP1 and PGC1α. We also observed an upregulation of AMPKα and ACC1/2 phosphorylation on FO supplementation in SWAT suggesting a role of AMPK-PGC1α-UCP1 axis in beiging of adipose tissue. On the other hand, corn oil supplementation did not show any improvements in adipose tissue metabolism in both the depots of adipose tissue. The results were analysed using one-way ANOVA followed by Tukey's test in Graphpad Prism 5.0. Combined together our results suggest that n-3 PUFAs exert their anti-obesity effect by regulating adipokine secretion and inducing beiging of SWAT, hence increasing energy expenditure via thermogenic upregulation.

A role for alternative splicing in circadian control of exocytosis and glucose homeostasis.

The circadian clock is encoded by a negative transcriptional feedback loop that coordinates physiology and behavior through molecular programs that remain incompletely understood. Here, we reveal rhythmic genome-wide alternative splicing (AS) of pre-mRNAs encoding regulators of peptidergic secretion within pancreatic β cells that are perturbed in Clock-/- and Bmal1-/- β-cell lines. We show that the RNA-binding protein THRAP3 (thyroid hormone receptor-associated protein 3) regulates circadian clock-dependent AS by binding to exons at coding sequences flanking exons that are more frequently skipped in clock mutant β cells, including transcripts encoding Cask (calcium/calmodulin-dependent serine protein kinase) and Madd (MAP kinase-activating death domain). Depletion of THRAP3 restores expression of the long isoforms of Cask and Madd, and mimicking exon skipping in these transcripts through antisense oligonucleotide delivery in wild-type islets reduces glucose-stimulated insulin secretion. Finally, we identify shared networks of alternatively spliced exocytic genes from islets of rodent models of diet-induced obesity that significantly overlap with clock mutants. Our results establish a role for pre-mRNA alternative splicing in β-cell function across the sleep/wake cycle.

Lessons from rodent gastric bypass model of enteric hyperoxaluria

The aim of the article is to review studies on bone health and oxalate metabolism/therapeutics in the obese rodent model of Roux-en-Y gastric bypass (RYGB) and examine pathways to decrease procedural morbidity. Compared with controls, RYGB rodents have up to 40-fold more fat in their stool (steatorrhea) which positively correlates to increased urinary oxalate. These unabsorbed intestinal fatty acids bind calcium and prevent gut calcium oxalate formation, increasing soluble luminal oxalate availability and absorption (enteric hyperoxaluria). When intraluminal fecal fat exceeded about 175 mg/24 h in our model, more paracellular and transcellular oxalate transport across the distal colon occurred. Increasing dietary calcium and colonization with Oxalobacter formigenes reduced hyperoxaluria, whereas vitamin B6 supplementation did not. RYGB animals, when severely calcium deficient, had bone mineral density loss that could not be rescued with vitamin D supplementation. The findings of hyperoxaluria, steatorrhea, and decreased bone mineral density are seen in both human and rodent RYGB. Our model suggests that a low-fat, low-oxalate diet combined with calcium supplementation can decrease urinary oxalate and improve skeletal bone health. Our model is a useful tool to study renal and bone RYGB effects. Studies of longer duration are required to further evaluate mechanisms of disease and durability of therapeutics.

Differential Expression of Ormdl Genes in the Islets of Mice and Humans with Obesity

SummaryThe orosomucoid-like (Ormdl) proteins play a critical role in sphingolipid homeostasis, inflammation, and ER stress, all of which are associated with obesity and βcell dysfunction. However, their roles in β cells and obesity remain unknown. Here, we show that islets from overweight/obese human donors displayed marginally reduced ORMDL1-2 expression, whereas ORMDL3 expression was significantly downregulated compared with islets from lean donors. In contrast, Ormdl3 was substantially upregulated in the islets of leptin-deficient obese (ob/ob) mice compared with lean mice. Treatment of ob/ob mice and their islets with leptin markedly reduced islet Ormld3 expression. Ormdl3 knockdown in a β cell line induced expression of pro-apoptotic markers, which was rescued by ceramide synthase inhibitor fumonisin B1. Our results reveal differential expression of Ormdl3 in the islets of a mouse model and humans with obesity, highlight the potential effect of leptin in this differential regulation, and suggest a role for Ormdl3 in β cell apoptosis.

1817-P: Elafibranor and Glucagon-Like Peptide-1 Receptor Agonists Synergize to Attenuate Hepatic Inflammation and Fibrosis in a Rodent Model of Obesity, Insulin Resistance, and NASH

Elafibranor and GLP-1 receptor agonists synergize to attenuate hepatic inflammation and fibrosis in a rodent model of obesity, insulin resistance and NASH. Liver steatosis contributes to the development of hepatic insulin resistance and is present in the majority of T2DM patients, who are 50 or older. Therefore, many NAFLD patients with diabetes are currently treated with the antidiabetics, including GLP-1 receptor agonists (GLP-1RA). Elafibranor (ELA), a phase 3 candidate for the treatment of NASH, ameliorates insulin sensitivity and lowers HbA1c in patients with NASH-associated T2DM. The aim of our study was to evaluate the pharmacological benefit of combining GLP-1RA and ELA in the context of NASH-associated insulin resistance. GLP-1RA administration induced body weight loss, reduced insulinemia, HOMA-IR and liver steatosis in obese mice with NASH and insulin resistance, but its action on liver fibrosis was negligible. ELA co-administration allowed for GLP-1RA dose reduction and resolved all NASH features. Food intake was also normalized at reduced GLP-1RA doses. Plasma CRP concentration was reduced by 56% in mice that received the combination treatment. Transcriptomic analyses revealed that the synergism between ELA and GLP-1RA in the liver was limited to the modulation of the inflammatory pathways with no effect on metabolic genes. Since ELA and GLP-1RA also synergize in vitro to reduce TNFa secretion in LPS-activated THP1 macrophages, we postulate that both drugs have a direct action on inflammatory cells in the liver. Further analyses to characterize ELA and GLP-1RA effects on innate and adaptive immune responses will be presented. Conclusion: ELA and GLP-1RA synergize to reduce hepatic inflammation and fibrosis in a model of NASH and obesity. These results suggest a potential therapeutic interest of combining ELA and GLP-1RA for the treatment of T2DM in NASH patients. Disclosure V. Legry: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. E. Descamps: Employee; Self; GENFIT. Employee; Spouse/Partner; GENFIT. Stock/Shareholder; Spouse/Partner; GENFIT. Stock/Shareholder; Self; GENFIT. S. Debaecker: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. N. Stankovic-Valentin: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. P. Parroche: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. N. Degallaix: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. P. Poulain: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT. B. Staels: Consultant; Self; Genfit. R. Walczak: Employee; Self; GENFIT. Stock/Shareholder; Self; GENFIT.

151-OR: Radiologic Evidence that Hypothalamic Tissue Is Abnormal in Adults with Obesity and Type 2 Diabetes or Impaired Glucose Homeostasis

Gliosis, a cellular response to injury in neural tissue, is linked to diet-induced obesity in rodent models. Growing evidence also implicates reactive gliosis and inflammation of the mediobasal hypothalamus (MBH) as a potential mechanism connecting obesity to insulin resistance. We tested for radiologic evidence of MBH gliosis in humans in relation to impaired glucose homeostasis and type 2 diabetes (T2D), independent of obesity. Adults with obesity and 1) T2D not on insulin (N=17), 2) impaired glucose tolerance (IGT; N=21), or 3) normal glucose tolerance (NGT; N=29) by OGTT underwent magnetic resonance imaging to measure mean bilateral T2 relaxation time (ms) in the MBH and 3 control regions. Longer T2 relaxation time is a marker of gliosis. Groups were matched for race, sex, BMI and % body fat (P=0.99), but age differed (T2D 54 ± 8 y, IGT 46 ± 11 y, NGT 45 ± 12 y; P=0.02). Group differences in T2 relaxation time varied by brain region (interaction: chi2(6) = 65, P<0.0001, adjusted for sex and age). Bonferroni-corrected post-tests confirmed that MBH, but not control region, T2 relaxation times were longer in T2D (180 ± 26 ms) than IGT (160 ± 26 ms, P<0.0001) or NGT (152 ± 17 ms, P<0.0001) groups. Among all 67 subjects, fasting glucose, 2-hr post-glucose, and hemoglobin A1c values were each positively associated with MBH, but not control region, T2 relaxation times (interactions by region all P< 0.0001, MBH all P< 0.0001, control regions all NS). Among the 50 subjects without T2D, interactions remained significant (all P<0.0001), and greater 2-hr post-glucose and hemoglobin A1c were associated with longer MBH T2 relaxation times (β = 0.22 ms, P<0.0001 and β = 14.8 ms, P=0.002, respectively) whereas a trend was present for fasting glucose concentrations (β = 0.38 ms, P=0.06). These data provide novel evidence that the degree of inflammation and gliosis in glucose-regulating areas of the brain is related to impaired glucose homeostasis and T2D in adults with obesity. Disclosure J.L. Rosenbaum: None. L.E. Sewaybricker: None. S. Chandrasekaran: None. M. De Leon: None. M. Webb: None. S.J. Melhorn: None. E. Schur: None. Funding American Diabetes Association (1-17-ICTS-085 to E.S.)

Energy Restriction Decreases Triglyceride Turnover in Subcutaneous and Visceral Adipose Tissue, but Has No Effect on Hepatic De Novo Lipogenesis in Obese Zucker Rats

Abstract Objectives Obesity is associated with increased hepatic de novo lipogenesis (DNL) and altered triglyceride (TG) turnover. A previous trial in male Sprague Dawley rats demonstrated that both energy restriction and higher protein diets downregulate hepatic DNL. It is unknown whether energy restriction and higher protein diets alter kinetic measures of lipid metabolism in obese rodents. The present study examined the effects of energy restriction and dietary protein content on tissue-specific lipid kinetics in obese Zucker rats. Methods Six-week-old female obese Zucker rats (Leprfa+/fa+; n = 48) were randomized into one of four groups: ad libitum (AL) standard AIN-93 M diet (14% protein, 9% fat, 3 mg cholesterol/100 g feed), 60% energy-restricted (ER) diet, ad libitum high protein (AL + PRO) modified AIN-93 M diet (35% protein, 9% fat, 7.2 mg cholesterol/100 g feed), or a 60% energy-restricted high protein (ER + PRO) diet. Using 2H2O labeling and mass isotopomer distribution analysis, DNL, TG turnover, and de novo cholesterol synthesis were measured in hepatic, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) after 10 weeks of feeding. Two-way ANOVA and post-hoc Tukey pair-wise comparisons were performed. Results Energy restriction, independent of protein content, resulted in less body mass gain (main effect, P < 0.05), although there were no differences in body fat % (ER: 50.8 ± 2.8%, ER + PRO: 50.5 ± 3.7%, AL: 47.3 ± 5.3%, AL + PRO: 50.0 ± 5.3%; P > 0.05). Energy restriction decreased TG turnover in SAT and VAT (main effect, P < 0.05), increased the contribution from DNL versus other sources to newly deposited TG in VAT (P < 0.01), did not change total DNL in VAT or liver (P > 0.05) but reduced DNL in SAT (P < 0.01), and increased hepatic, SAT, and VAT de novo cholesterol synthesis (P < 0.01). Dietary protein had no effect on lipid kinetics. Conclusions In obese Zucker rats, hepatic DNL was not altered by energy restriction or higher protein feeding. However, energy restriction did decrease TG turnover in SAT and VAT. In a leptin-deficient rodent model of obesity, energy restriction had differential effects on various measures of lipid metabolism. Funding Sources DMRP/USAMRDC. Views expressed are those of the authors and do not reflect the official policy of the Army, DoD, or U.S. Government.