Animal Model Of Diet-induced Obesity Research Articles

Dulaglutide rescues the elevated testicular dysfunction in a mouse model of high-fat diet-induced obesity

Obesity is a well-known risk factor for testicular function; however, dulaglutide's effect on the testis in obesity has received little attention. Currently, clinicians prescribe the antidiabetic drug dulaglutide only off-label for weight management in non-diabetics. Investigating the impact of this novel compound on obesity is critical for determining whether it has any disruptive effects on testicular cells. We used a well-known animal model of high-fat diet-induced obesity in this investigation, and testicular dysfunction was determined by sperm DNA damage, spermatocyte chromosomal abnormalities, and spermiogram analysis. Following a 12-week high-fat diet challenge, mice were randomly assigned to dulaglutide (0.6 mg/kg/day) or saline treatments for five weeks. Testes and sperm cells were collected 24 h after the last dulaglutide injection. Untreated obese mice had a lower testes/body weight ratio, more sperm DNA damage, diakinesis-metaphase I chromosomal abnormalities, a lower sperm count/motility, more cell morphological defects, and an altered testicular redox balance. In obese mice, dulaglutide injection efficiently restored all disturbed parameters to their control levels. Dulaglutide injection into healthy mice exhibited no significant harmful effects at the applied regimen. As a result, we infer that dulaglutide therapy might bring obese men additional benefits by recovering testicular dysfunction induced by obesity.

Linking adipose tissue eosinophils, IL-4, and leptin in human obesity and insulin resistance.

BACKGROUNDObesity is a multifactorial disease with adverse health implications including insulin resistance (IR). In patients with obesity, the presence of high circulating levels of leptin, deemed hyperleptinemia, is associated with IR. Recent data in mice with diet-induced obesity (DIO) show that a partial reduction in leptin levels improves IR. Additional animal studies demonstrate that IL-4 decreases leptin levels. In rodents, resident adipose tissue eosinophils (AT-EOS) are the main source of IL-4 and are instrumental in maintaining metabolic homeostasis. A marked reduction in AT-EOS content is observed in animal models of DIO. These observations have not been explored in humans.METHODSWe analyzed AT from individuals with obesity and age-matched lean counterparts for AT-EOS content, IL-4, circulating leptin levels, and measures of IR.RESULTSOur results show that individuals with obesity (n = 15) had a significant reduction in AT-EOS content (P < 0.01), decreased AT-IL-4 gene expression (P = 0.02), and decreased IL-4 plasma levels (P < 0.05) in addition to expected IR (P < 0.001) and hyperleptinemia (P < 0.01) compared with lean subjects (n = 15). AT-EOS content inversely correlated with BMI (P = 0.002) and IR (P = 0.005). Ex vivo AT explants and in vitro cell culture of primary human mature adipocytes exposed to either IL-4 or EOS conditioned media produced less leptin (P < 0.05).CONCLUSIONOur results suggest that IL-4 acts as a link between EOS, AT, and leptin production. Future studies exploring this interaction may identify an avenue for the treatment of obesity and its complications through amelioration of hyperleptinemia.TRIAL REGISTRATIONClinicaltrials.gov NCT02378077 & NCT04234295.

Crocus sativus tepals extract suppresses subcutaneous adipose tissue hypertrophy and improves systemic insulin sensitivity in mice on high-fat diet.

Obesity is a pressing problem worldwide for which standard therapeutic strategies have limited effectiveness. The use of natural products seems to be a promising approach to alleviate obesity and its associated complications. The tepals of Crocus sativus (Cr) plant, usually wasted in saffron production, are an unexplored source of bioactive compounds. Our aim was to elucidate the mechanisms of Cr tepals extract in obesity by investigating its effects on adipocyte differentiation, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) hypertrophy, and lipid metabolism in an animal model of diet-induced obesity. To this end, mouse 3T3-F442A preadipocytes were treated with Cr tepals extract and the expression of adipocyte differentiation genes was determined. Caloric intake, body mass, triglycerides, systemic insulin sensitivity, histology, insulin signaling, and lipid metabolism in VAT and SAT were analyzed in mice fed a 60% fat diet for 14 weeks and treated orally with Cr tepals extract during the last 5 weeks of the diet. We demonstrated for the first time that Cr tepals extract inhibits adipocyte differentiation in vitro. The animal model confirmed that oral treatment with Cr tepals extract results in weight loss, improved systemic insulin sensitivity, lower triglycerides, and improved lipid peroxidation. The suppressive effect of Cr tepals extract on adipocyte hypertrophy and inflammation was observed only in SAT, which, together with preserved SAT insulin signaling, most likely contributed to improved systemic insulin sensitivity. Our results suggest the functionality of SAT as a possible target for the treatment of obesity and its complications.

Vitamin D and obesity.

An inverse association between vitamin D status and obesity has been reported across diverse populations and age groups in humans. In animal model of diet-induced obesity, dysregulation of vitamin D metabolism has been observed. However, the causal relationship between vitamin D status and obesity is not conclusive. Several explanations, such as volumetric dilution, sequestration of vitamin D into adipose tissue, and limited sunlight exposure, have been suggested as the underlying mechanisms linking poor vitamin D status and obesity. Vitamin D can modulate adipose tissue biology, spanning from adipocyte differentiation to adipocyte apoptosis and energy metabolism, indicating its potential impact on adiposity. In this chapter, we will review the prevalence of vitamin D deficiency and determinants of vitamin D deficiency among different populations, as well as changes in vitamin D metabolism associated with obesity. Additionally, we will review vitamin D's regulation of adipogenesis and lipogenesis at the cellular level in order to gain a deeper understanding of the underlying mechanisms linking vitamin D levels and obesity.

Nutritional supplement of Lepidium sativum L. seeds alleviates metabolic disorders and inflammatory responses in high-fat diet-induced obese rats via modulating AMPK/SREBP-1c of PPARγ signaling pathway

BackgroundObesity is a multifactorial chronic non-communicable disease that affects more than one- third of the world population. It represents a burden on human health in both developed and developing countries. Nowadays there is an urgent need for effective natural alternatives to manage obesity. This study aimed at exploring the fundamental molecular processes and contributive pathways of the hydroalcoholic extract of Lepidium sativum, L. seeds (LP) to manage weight gain with its accompanied metabolic complications in a high-fat diet-induced obesity animal model. MethodsDifferent doses of the hydroalcoholic extract were investigated for adipogenesis inhibition in liver tissues through Peroxisome-proliferator-activated receptor-gamma (PPARγ) transcriptional activity and mitochondrial phosphorylation of 5′AMP-activated protein kinase (AMPK) using western blot. Sterol regulatory element-binding protein (SREBP)-1c which plays a role in regulating cellular free fatty acid homeostasis via fatty acid oxidation and lipogenesis was evaluated using RT-qPCR gene analysis. Furthermore, Analyses of alterations in body weight and serum biomarkers such as triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), insulin, leptin and adiponectin were used to assess the anti-obesity effect. The protective seeds’ impact on hepatic tissues was further assessed by histopathological examination. The bioactive metabolites profiling was conducted via HPLC/ESI/PDA/MS-MS. ResultsLP effectively modulated PPARγ transcriptional activity via activation of mitochondrial phosphorylation of AMPK. Moreover, RT-qPCR gene analysis presented suppression of nuclear expression of SREBP-1c in dose-dependent method related to control group. Furthermore, it was revealed that LP moderated serum lipid profile, glycemic profile, leptin, and adiponectin. In addition, it reduced liver injury through decreasing ALT and AST enzymes in serum, upregulating liver antioxidant enzyme glutathione, and downregulating oxidative stress manifested in decreased malondialdehyde (MDA) levels. The anti-inflammatory activity was confirmed by declining in proinflammatory cytokine leukotriene B4 (LT-B4). ConclusionThis study is the first to report the potential impact of nutritional supplementation of Lepidium sativum seeds (400 mg/kg) to alleviate metabolic disorders and inflammatory responses in high-fat diet-induced obese rats via modulating AMPK/SREBP-1c of the PPARγ signaling Pathway.

Conferring liver selectivity to a thyromimetic using a novel nanoparticle increases therapeutic efficacy in a diet-induced obesity animal model.

Optimization of metabolic regulation is a promising solution for many pathologies, including obesity, dyslipidemia, type 2 diabetes, and inflammatory liver disease. Synthetic thyroid hormone mimics-based regulation of metabolic balance in the liver showed promise but was hampered by the low biocompatibility and harmful effects on the extrahepatic axis. In this work, we show that specifically directing the thyromimetic to the liver utilizing a nanogel-based carrier substantially increased therapeutic efficacy in a diet-induced obesity mouse model, evidenced by the near-complete reversal of body weight gain, liver weight and inflammation, and cholesterol levels with no alteration in the thyroxine (T4) / thyroid stimulating hormone (TSH) axis. Mechanistically, the drug acts by binding to thyroid hormone receptor β (TRβ), a ligand-inducible transcription factor that interacts with thyroid hormone response elements and modulates target gene expression. The reverse cholesterol transport (RCT) pathway is specifically implicated in the observed therapeutic effect. Overall, the study demonstrates a unique approach to restoring metabolic regulation impacting obesity and related metabolic dysfunctions.

Ameliorative effects of gallic acid on GLUT-4 expression and insulin resistance in high fat diet-induced obesity animal model mice, Mus musculus.

The online version contains supplementary material available at 10.1007/s40200-023-01194-5.

Butyrate Improves Neuroinflammation and Mitochondrial Impairment in Cerebral Cortex and Synaptic Fraction in an Animal Model of Diet-Induced Obesity.

Neurodegenerative diseases (NDDs) are characterized by cognitive impairment and behavioural abnormalities. The incidence of NDDs in recent years has increased globally and the pathological mechanism is not fully understood. To date, plentiful evidence has showed that metabolic alterations associated with obesity and related issues such as neuroinflammation, oxidative stress and mitochondrial dysfunction may represent an important risk factor, linking obesity and NDDs. Numerous studies have indicated a correlation between diet and brain activities. In this context, a key role is played by mitochondria located in the synaptic fraction; indeed, it has been shown that high-fat diets cause their dysfunction, affecting synaptic plasticity. In this scenario, the use of natural molecules that improve brain mitochondrial function represents an important therapeutic approach to treat NDDs. Recently, it was demonstrated that butyrate, a short-chain fatty acid is capable of counteracting obesity in an animal model, modulating mitochondrial function. The aim of this study has been to evaluate the effects of butyrate on neuroinflammatory state, oxidative stress and mitochondrial dysfunction in the brain cortex and in the synaptic fraction of a mouse model of diet-induced obesity. Our data have shown that butyrate partially reverts neuroinflammation and oxidative stress in the brain cortex and synaptic area, improving mitochondrial function and efficiency.

Carotenoids: a missing link between Gut Microbiota and Obesity

Carotenoids are naturally occurring red, orange, and yellow pigments found mainly in fruits and vegetables. They may function as vitamin A precursors, have important antioxidant, immunological or metabolic functions. The overall absorption efficiency of carotenoids from whole foods is considerably lower in the small intestine. When carotenoids enter the colon together with indigestible dietary compounds, they can become a potential substrate for microbial fermentation. Carotenoids can be further released, or additional conversions can happen within colon epithelial cells. This study's overall objective is to determine the impact of carotenoids on obesity-associated gut dysfunction (microbial dysbiosis, impaired intestinal barrier function, and low-grade inflammation). Our central hypothesis is that carotenoids escaping the absorption in the small intestine can be transformed by the gut microbiota in the colon. First, we examined the molecular mechanisms behind the anti-inflammatory action of one of the major dietary carotenoid, β-carotene (BC), and its role in maintaining gut barrier integrity using in vitro intestinal epithelial cell model. We found out that BC could improve colonic inflammation by blocking inflammatory transcription factors and subsequently reducing pro-inflammatory cytokines in the colon. We have also seen that BC could improve gut barrier integrity within colon epithelial cells when cells challenged with endotoxins. Next, we determined the impact of microbial metabolism and fermentation on the carotenoids present in the colon using an ex vivo fecal fermentation model. We demonstrated that BC would be metabolized by the microbiome in human stool samples. Finally, we plan to examine the effect of carotenoid-rich diet on obesity-associated gut dysfunction, metabolic endotoxemia, and gut barrier in vivo using a murine model. We will characterize carotenoid-induced changes in the gut microbiota utilizing shotgun sequencing and multi-omic approaches, including metabolomics and shotgun metagenomics in the diet-induced obesity animal model.

Skeletal Muscle Proteomic Profile Revealed Gender-Related Metabolic Responses in a Diet-Induced Obesity Animal Model.

Obesity is a chronic, complex pathology associated with a risk of developing secondary pathologies, including cardiovascular diseases, cancer, type 2 diabetes (T2DM) and musculoskeletal disorders. Since skeletal muscle accounts for more than 70% of total glucose disposal, metabolic alterations are strictly associated with the onset of insulin resistance and T2DM. The present study relies on the proteomic analysis of gastrocnemius muscle from 15 male and 15 female C56BL/J mice fed for 14 weeks with standard, 45% or 60% high-fat diets (HFD) adopting a label-free LC–MS/MS approach followed by bioinformatic pathway analysis. Results indicate changes in males due to HFD, with increased muscular stiffness (Col1a1, Col1a2, Actb), fiber-type switch from slow/oxidative to fast/glycolytic (decreased Myh7, Myl2, Myl3 and increased Myh2, Mylpf, Mybpc2, Myl1), increased oxidative stress and mitochondrial dysfunction (decreased respiratory chain complex I and V and increased complex III subunits). At variance, females show few alterations and activation of compensatory mechanisms to counteract the increase of fatty acids. Bioinformatics analysis allows identifying upstream molecules involved in regulating pathways identified at variance in our analysis (Ppargc1a, Pparg, Cpt1b, Clpp, Tp53, Kdm5a, Hif1a). These findings underline the presence of a gender-specific response to be considered when approaching obesity and related comorbidities.

Skeletal Muscle Proteomic Profile Revealed Gender-Related Metabolic Responses in a Diet-Induced Obesity Animal Model

Skeletal Muscle Proteomic Profile Revealed Gender-Related Metabolic Responses in a Diet-Induced Obesity Animal Model

\u03c9-3PUFA supplementation ameliorates adipose tissue inflammation and insulin-stimulated glucose disposal in subjects with obesity: a potential role for apolipoprotein E

BackgroundLong chain omega-3 polyunsaturated fatty acids (ω-3PUFA) supplementation in animal models of diet-induced obesity has consistently shown to improve insulin sensitivity. The same is not always reported in human studies with insulin resistant (IR) subjects with obesity.ObjectiveWe studied whether high-dose ω-3PUFA supplementation for 3 months improves insulin sensitivity and adipose tissue (AT) inflammation in IR subjects with obesity.MethodsThirteen subjects (BMI = 39.3 ± 1.6 kg/m2) underwent 80 mU/m2·min euglycemic-hyperinsulinemic clamp with subcutaneous (Sc) AT biopsy before and after 3 months of ω-3PUFA (DHA and EPA, 4 g/daily) supplementation. Cytoadipokine plasma profiles were assessed before and after ω-3PUFA. AT-specific inflammatory gene expression was evaluated on Sc fat biopsies. Microarray analysis was performed on the fat biopsies collected during the program.ResultsPalmitic and stearic acid plasma levels were significantly reduced (P < 0.05) after ω-3PUFA. Gene expression of pro-inflammatory markers and adipokines were improved after ω-3PUFA (P < 0.05). Systemic inflammation was decreased after ω-3PUFA, as shown by cytokine assessment (P < 0.05). These changes were associated with a 25% increase in insulin-stimulated glucose disposal (4.7 ± 0.6 mg/kg ffm•min vs. 5.9 ± 0.9 mg/kg ffm•min) despite no change in body weight. Microarray analysis identified 53 probe sets significantly altered post- ω-3PUFA, with Apolipoprotein E (APOE) being one of the most upregulated genes.ConclusionHigh dose of long chain ω-3PUFA supplementation modulates significant changes in plasma fatty acid profile, AT, and systemic inflammation. These findings are associated with significant improvement of insulin-stimulated glucose disposal. Unbiased microarray analysis of Sc fat biopsy identified APOE as among the most differentially regulated gene after ω-3PUFA supplementation. We speculate that ω-3PUFA increases macrophage-derived APOE mRNA levels with anti-inflammatory properties.

Long-term supplementation with phenolic compounds from jaboticaba (Plinia jaboticaba (Vell.) Berg) reduces adiposophaty and improves glucose, lipid, and energy metabolism

Obesity is a critical public health problem worldwide that has been associated to non-communicable diseases (NCD), such as type 2 diabetes (T2DM), non-alcoholic fatty lipid diseases (NAFLD) and inflammatory diseases. Polyphenols from several food sources have been studied as one option against these health problems. Sabara jaboticaba (Plinia jaboticaba (Vell.) Berg) is a Brazilian berry rich in ellagic acid derivatives and anthocyanins. Here we investigated the effects of a phenolic-rich extract from Sabara jaboticaba (PEJ) in a diet-induced obesity animal model. PEJ at two doses, 50 mg gallic acid equivalent (GAE)/kg body weight (BW) and 100 mg GAE/kg BW, were administered by daily gavage to obese C57BL/6J mice for 14 weeks. PEJ prevented the excessive body weight and adiposity, adipocyte hypertrophy, inflammation, hyperglycemia, glucose intolerance, insulin resistance, hypercholesterolemia, and hepatic lipid accumulation, as well as increased energy expenditure. In conclusion, polyphenols from Sabara jaboticaba presented several powerful therapeutic properties relevant for fighting obesity and associated health problems.

Lycopene is superior to moringa in improving fertility markers in diet-induced obesity male rats.

Obesity is a condition of chronic tissue inflammation and oxidative stress that poses as a risk factor for maleinfertility. Moringa oleifera oil extract is known to have cholesterol-loweringproperties and a potential to treat obesity, while lycopene is a potent antioxidant. We hypothesize that Moringa or lycopene may improve male fertility markers in an animal model of diet-induced obesity. Male Albino rats (n=60) were randomized to receive regular chow (RC) or high-fat diet (HFD) for 12weeks (n=30 each). Animals in each arm were further randomized to receive gavage treatment with corn oil (vehicle), lycopene (10mg/kg), or Moringa (400mg/kg) for four weeks starting on week 9 (n=10 each). Animals were sacrificed at 12weeks, and blood was collected to assess lipid profile, serum testosterone, and gonadotropin levels. The testes and epididymides were removed for sperm analysis, oxidative stress and inflammatory markers, and histopathological assessment. In comparison to their RC littermates, animals on HFD showed an increase in body weights, serum lipids, testosterone and gonadotrophin levels, testicular oxidative stress and inflammatory markers, as well as sperm abnormalities and disrupted testicular histology. Moringa or lycopene reduced body weight, improved oxidative stress, and male fertility markers in HFD-fed animals with lycopene exhibiting better anti-antioxidant and anti-lipidemic effects. Lycopene is superior to Moringa in improving male fertility parameters, possibly by attenuating oxidative stress.

Polylactose Exhibits Prebiotic Activity and Reduces Adiposity and Nonalcoholic Fatty Liver Disease in Rats Fed a High-Fat Diet

Prebiotic dietary fibers change the intestinal microbiome favorably and provide a health benefit to the host. Polylactose is a novel fiber, synthesized by extrusion of lactose. We evaluated its prebiotic activity by determining its fermentability, effect on the microbiota, and effects on adiposity and liver lipids in a diet-induced obesity animal model. Male Wistar rats (4-5 wk old) were fed normal-fat (NF, 25% fat energy) or high-fat (HF, 51% fat energy) diets containing different fibers (6% fiber of interest and 3% cellulose, by weight), including cellulose (NFC and HFC, negative and positive controls, respectively), polylactose (HFPL), lactose matched to residual lactose in the HFPL diet, and 2established prebiotic fibers: polydextrose (HFPD) and fructooligosaccharide (HFFOS). After 10 wk of feeding, organs were harvested and cecal contents collected. HFPL animals had greater cecum weight (3 times greater than HFC) and lower cecal pH (∼1pH unit lower than HFC) than all other groups, suggesting that polylactose is more fermentable than other prebiotic fibers (HFPD, HFFOS; P <0.05). HFPL animals also had increased taxonomic abundance of the probiotic species Bifidobacterium in the cecum relative to all other groups (P <0.05). Epididymal fat pad weight was significantly decreased in the HFPL group (29% decrease compared with HFC) compared with all other HF groups (P <0.05) and did not differ from the NFC group. Liver lipids and cholesterol were reduced in HFPL animals when compared with HFC animals (P <0.05). Polylactose is a fermentable fiber that elicits a beneficial change in the gut microbiota as well as reducing adiposity in rats fed HF diets. These effects of polylactose were greater than those of 2 established prebiotics, fructooligosaccharide and polydextrose, suggesting that polylactose is a potent prebiotic.

Potential Role of Hypothalamic and Plasma Ghrelin in the Feeding Behavior of Obese Type 2 Diabetic Rats with Intraventricular Glucagon-Like Peptide-1 Receptor Agonist Intervention

Objective: To investigate the relationship of central and peripheral ghrelin during an exendin-4 (Ex-4) intervention to feeding in obese type 2 diabetic rodents. Methods: Animal models of diet-induced obesity (DIO) and type 2 diabetes were developed using male Sprague-Dawley rats fed with a high-fat diet and induced into DIO-streptozotocin diabetic rats. Ex-4 or the glucagon-like peptide-1 (GLP-1) receptor agonist exendin fragment-[9-39] (Ex-9) was intracerebroventricularly (ICV) administered. Multivariate linear regression analysis was performed to investigate potential predictors of food intake after Ex-4 administration. Results: ICV administration of Ex-4 significantly inhibited feeding and decreased weight, plasma active ghrelin, hypothalamic ghrelin, and gastric ghrelin levels. The changes in hypothalamic ghrelin and plasma ghrelin could predict the amount of 8-h average food intake. Central preadministration of Ex-9 followed by treatment with Ex-4 could inhibit the decrease in feeding at 0.5, 2, and 8 h. It could also inhibit the decrease in hypothalamic ghrelin at 0.5, 2, and 8 h, as well as in plasma and gastric ghrelin at 2 and 8 h. Conclusions: In a GLP-1 receptor-dependent manner, central and peripheral ghrelin play a vital role in the inhibition of feeding by Ex-4 administration. Hypothalamic ghrelin, but not plasma ghrelin, may be involved in central Ex-4 inhibition of feeding in the very early feeding period.

Can eosinophils in adipose tissue add fuel to the fire?

In inguinal adipose tissue, beige adipocytes are interspersed among white adipocytes and in close communication with dynamic populations of immune cells. Recent data have demonstrated that anti-inflammatory macrophages (M2) increase thermogenic activity of beige adipocytes, although the mechanism is currently under debate. ILC2, cells via secretion, of methionine enkephalin peptide were found to be able to increase beige thermogenesis. Knights et al. have recently generated a whole-body knock-out of KLF3 (KLF3-/-) to explore its contribution to thermogenesis and weight gain in a diet-induced obesity animal model.

Lactobacillus plantarum Shinshu N-07 isolated from fermented Brassica rapa L. attenuates visceral fat accumulation induced by high-fat diet in mice

Lactobacillus plantarum Shinshu N-07 (N07) and Lactobacillus curvatus #4G2 (#4G2) were isolated from fermented Brassica rapa L. and selected as promising probiotics with anti-adiposity activities based on in vitro assays. The anti-adiposity effects of these two strains were investigated using a diet-induced obesity animal model. Epididymal adipose tissue weight and adipocyte area were significantly lower and serum triglycerides and glucose tended to be lower in mice fed the high-fat diet supplemented with N07 compared with those fed the unsupplemented high-fat diet. Strain N07 suppressed hepatic steatosis, with accompanying downregulation of lipogenic genes in the liver. Expression of inflammatory cytokines and macrophage infiltration markers tended to be suppressed by N07 supplementation. Upregulation of uncoupling protein-1 in epididymal adipose tissue by N07 suggested that the transformation of white adipose tissue to brown might have been induced. Intestinal microbiota analysis revealed that a decrease in abundance of family S24-7 (phylum Bacteroidetes) following ingestion of the high-fat diet was partly recovered by supplementation with N07. Changes in those parameters were not observed in mice fed the high-fat diet supplemented with strain #4G2, suggesting strain specificities. Thus, N07 is a potential probiotic strain that could be used to develop functional foods that attenuate visceral fat accumulation after an appropriate human intervention trial.

Nucleus accumbens cytoarchitecture predicts weight gain in children

The prevalence of obesity in children and adolescents worldwide has quadrupled since 1975 and is a key predictor of obesity later in life. Previous work has consistently observed relationships between macroscale measures of reward-related brain regions (e.g., the nucleus accumbens [NAcc]) and unhealthy eating behaviors and outcomes; however, the mechanisms underlying these associations remain unclear. Recent work has highlighted a potential role of neuroinflammation in the NAcc in animal models of diet-induced obesity. Here, we leverage a diffusion MRI technique, restriction spectrum imaging, to probe the microstructure (cellular density) of subcortical brain regions. More specifically, we test the hypothesis that the cell density of reward-related regions is associated with obesity-related metrics and early weight gain. In a large cohort of nine- and ten-year-olds enrolled in the Adolescent Brain Cognitive Development (ABCD) study, we demonstrate that cellular density in the NAcc is related to individual differences in waist circumference at baseline and is predictive of increases in waist circumference after 1 y. These findings suggest a neurobiological mechanism for pediatric obesity consistent with rodent work showing that high saturated fat diets increase gliosis and neuroinflammation in reward-related brain regions, which in turn lead to further unhealthy eating and obesity.

Changes of fat-mass and obesity-associated protein expression in the hippocampus in animal models of high-fat diet-induced obesity and D-galactose-induced aging

Fat-mass and obesity-associated protein (Fto) is highly expressed in the brain including, the hippocampus, and its expression is significantly decreased in the brain of Alzheimer’s disease patients. In the present study, we measured Fto immunoreactivity and protein levels in the hippocampus of obese and aged mice, which were induced by high-fat diet for 12 weeks and D-galactose treatment for 10 weeks, respectively. The obesity and aging phenotypes were assessed by physiological parameters and Morris water maze test, respectively. High fat diet fed mice showed significant increases in body weight and blood glucose levels compared to that in the control or D-galactose-induced aged mice. In addition, treatment with D-galactose significantly decreased the spatial memory. Fto immunoreactivity in the control group was mainly detected in the pyramidal cells of the CA1 and CA3 regions and in the granule cells of the dentate gyrus. In the hippocampus of high-fat diet-fed mice, Fto immunoreactive structures were similarly found in the hippocampus compared to that in the control group, but Fto immunoreactivity in high-fat diet-fed mice was also found in the stratum oriens and radiatum of the CA1 and CA3 regions and the polymorphic layer of the dentate gyrus. In the hippocampus of D-galactose-induced aged mice, fewer Fto immunoreactive structures were detected in the granule cell layer of the dentate gyrus compared to the control group. Fto mRNA and protein levels based on quantitative real-time polymerase chain reaction and western blot assays were slightly increased in the hippocampus of high-fat diet-fed mice compared to that in control mice. In addition, Fto mRNA and protein levels were significantly decreased in the aged hippocampus compared to that in the control group. Fto protein levels are susceptible to the aging process, but not in the hippocampus of high-fat diet-induced obesity. The reduction of Fto in aged mice may be associated with reduced memory impairment in mice.