Lean Rats Research Articles

Effect of Age and Body Weight on the Maintenance Requirement of Lean and Obese Zucker Rats

The effect of age (34–215 days) and body weight (80–627 g) on the maintenance requirements of lean (n = 4) and obese (n = 4) Zucker rats was determined in 5 maintenance trials. The rats were fed a semipurified, 20% protein diet. The metabolizable energy intake (MEI) required for maintenance of body weight (BW) was determined in weekly intake-metabolism trials. Maintenance requirements [kilocalories MEI/(day·kilogram BW)] were lower (P < 0.01) for obese rats than for lean rats, and they decreased with age for both body types, respectively (Y = 206.23 - 0.3524 X; r = -0.547 and Y = 252.61 -0.4818 X; r = -0.649). Maintenance requirements (kilocalories MEI/day) of obese rats were lower (P < 0.01) than lean rats, respectively, when expressed in terms of grams body weight (Y = 7.03 + 0.1333 X; r = 0.994 and Y = 9.04 + 0.1441 X; r = 0.994), metabolic body size (kilogram0.75) (Y = -4.52 + 132.33 X; r = 0.989 and Y = 0.05 + 130.52 X; r = 0.992) or least squares, type-specific exponent [Y = 119.03 (kilogram0.77); r = 0.975 and Y = 120.87 (kilogram0.71); r = 0.986]. The results indicate that obese Zucker rats have lower maintenance requirements than their lean littermates and that maintenance requirements are as closely related to body weight as to metabolic body size or type-specific exponent for each body type.maintenance requirement Zucker rat voluntary activity metabolic body size

Variations of Blood Pressures in Lean Zucker Rats Fed Low or High Fat Diets

The purpose of this study was to determine whether lean (Fa/?) Zucker rats which exhibit greater metabolic efficiency in response to a high (48%) fat diet also exhibit hypertension. Twenty-nine lean (Fa/?) and eleven obese (fa/fa) Zucker rats were fed low (12% energy) and high (48% energy) fat diets. Food intake and weight change were recorded weekly to obtain an index of energy efficiency. After 6 wk, direct intra-arterial blood pressure was measured in conscious, unrestrained animals. Arterial blood was collected for analyses of plasma insulin and glucose. The high fat diet had no effect on blood pressure in obese rats, although obese animals fed both diets had significantly higher blood pressure than lean siblings. High fat feeding in lean rats unmasked a heterogeneity in blood pressure. Blood pressure in this group was significantly correlated with weight change, energy efficiency ratio and plasma glucose concentration. Lean rats fed the high fat diet with blood pressures above the group median exhibited significantly greater plasma insulin (P < 0.02) and glucose (P < 0.01) concentration and energy efficiency ratios (P < 0.01) than those with lower blood pressures. Thus, it appears that there were two groups of lean animals present, one of which was more phenotypically sensitive to high fat feeding than the other. This suggests a possible gene dosage effect of the fa allele in the Zucker rat model.

Elevated Neuropeptide Y in the Arcuate Nucleus of Young Obese Zucker Rats May Contribute to the Development of Their Overeating

Neuropeptide Y (NPY) mediates feeding behavior through a local hypothalamic network formed by the arcuate and paraventricular nuclei (the AP axis). In the hypothalamus, NPY is mainly synthesized in neurons of the arcuate nucleus. These neurons project to the paraventricular nucleus, the site where NPY has the strongest stimulatory effects on food intake of Sprague-Dawley rats. In the adult Zucker fatty rat (a genetic model of obesity with a well-established hyperphagia), NPY concentrations in these nuclei are higher than in its lean counterpart. We measured hypothalamic NPY before the appearance of altered eating behavior, e.g., in very young (16-d-old) lean and obese Zucker pups, and in pups at an age when overeating had begun, e.g., a few days after weaning at 30 d. At 30 d, NPY concentrations were significantly higher in obese than in lean rats in the arcuate nucleus (14.2 +/- 0.7 vs. 11.6 +/- 0.5 pmol/mg protein, P < 0.01). This difference was not observed at 16 d. A 160% increase was noted in the paraventricular nuclei of obese rats between 16 and 30 d of life compared with a 100% increase in the lean rats (P < 0.001). Neuropeptide Y concentration was greater in 30-d-old rats than in 16-d-old rats in other areas involved in the regulation of feeding behavior, such as the dorsomedian nuclei and lateral hypothalamus, but the values did not differ between genotypes. Higher NPY concentration was therefore detected early in young obese rats in the main hypothalamic site of NPY synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Intestinal Glucose Absorption Is Lower in Obese than in Lean Zucker Rats

Obese Zucker (fa/fa) rats had lower intestinal glucose absorption following an intragastric [U-14C]glucose load than lean (+/?) Zucker rats. In the fa/fa animals, the rate of oxidation of the tracer to 14CO2 was similar to that observed in their lean counterparts. Although there were no differences in the incorporation of the tracer in liver and skeletal muscle glycogen, the conversion and incorporation of [U-14C]glucose into tissue [14C]lipid was higher in the obese animals. Isolated enterocytes from lean and obese Zucker rats showed a similar capacity for [U-14C]glucose utilization. Reconstituted brush border membrane vesicles from obese Zucker rats showed a higher Vmax for glucose transport than those from their lean counterparts. The lower glucose absorption found in the fa/fa rats in vivo may contribute to the maintenance of normoglycemia in these animals.

BAT’s specific Micro-RNA or Novel approach for treatment of obesity: A hypothesis

Background: Type 2 Diabetes (T2D) is associated with coronary microvascular dysfunction, which is thought to contribute to compromised diastolic function, ultimately culminating in heart failure with preserved ejection fraction (HFpEF). The molecular mechanisms remain incompletely understood, and no early diagnostics are available. We sought to gain insight into biomarkers and potential mechanisms of microvascular dysfunction in obese mice (db/db) and lean rats (Goto-Kakizaki) pre-clinical models of T2D-associated diastolic dysfunction. Methods: The microRNA (miRNA) content of circulating Extracellular Vesicles (EVs) was assessed in T2D models to identify biomarkers of coronary microvascular dysfunction/rarefaction. The potential source of circulating EV-encapsulated miRNAs was determined, and the mechanisms of induction and the function of candidate miRNAs were assessed in Endothelial Cells (ECs). Results: We found an increase in miR-30d-5p and miR-30e-5p in circulating EVs that coincided with indices of coronary microvascular EC dysfunction (i.e., markers of oxidative stress, DNA damage/senescence) and rarefaction, and preceded echocardiographic evidence of diastolic dysfunction. These miRNAs may serve as biomarkers of coronary microvascular dysfunction as they are upregulated in ECs of the left ventricle of the heart, but not other organs, in db/db mice. Furthermore, the miR-30 family is secreted in EVs from senescent ECs in culture, and ECs with senescent-like characteristics are present in the db/db heart. Assessment of miR-30 target pathways revealed a network of genes involved in fatty acid biosynthesis and metabolism. Over-expression of miR-30e in cultured ECs increased fatty acid β-oxidation and the production of reactive oxygen species and lipid peroxidation while inhibiting the miR-30 family decreased fatty acid β-oxidation. Additionally, miR-30e over-expression synergized with fatty acid exposure to down-regulate the expression of eNOS, a key regulator of microvascular and cardiomyocyte function. Finally, the knock-down of the miR-30 family in db/db mice decreased markers of oxidative stress and DNA damage/senescence in the microvascular endothelium. Conclusion: MiR-30d/e represents early biomarkers and potential therapeutic targets that are indicative of the development of diastolic dysfunction and may reflect altered EC fatty acid metabolism and microvascular dysfunction in the diabetic heart.

Endogenous Sex Hormones Modulate the Analgesic Effect of Tramadol in Lean and High-Fat Diet-Induced Obese Wistar Rats: A Preclinical Molecular Approach

Introduction: Differences in pain thresholds may have implications in pain management, as they may account in part for the variability in analgesic requirements between individuals. We planned to investigate the influence of endogenous sex hormones on the analgesic modulation of tramadol in lean and high-fat diet-induced obese Wistar rats. Methods: The whole study was carried out on 48 adult Wistar rats (24 male: 12 obese and 12 lean and 24 female: 12 obese and 12 lean). Each male and female rat group was further subdivided into two groups (n = 6/group) and treated with normal saline/tramadol for 5 days. On the fifth day, 15 min after tramadol/normal saline treatment, animals were tested for pain perception toward noxious stimuli. Later, endogenous 17 beta-estradiol and free testosterone levels in serum were estimated through ELISA methods. Results: The present study revealed that female rats experienced more pain sensitivity to noxious stimuli compared to male rats. High-fat diet-induced obese rats experienced more pain sensations to noxious stimuli than lean rats. Obese male rats were found to have significantly low free testosterone and high 17 beta-estradiol levels compared to lean male rats. An increase in serum 17 beta-estradiol level led to increased pain sensation to noxious stimuli. While an increase in free testosterone level resulted in the lowering of pain sensation to noxious stimuli. Conclusion: The analgesic effect of tramadol was more pronounced in male rats compared to female rats. The analgesic effect of tramadol was more marked in lean rats compared to obese rats. Additional research to elucidate obesity-induced endocrine changes and the mechanisms driving sex hormones in pain perception is needed to foster future interventions to reduce disparities in pain.

Relationship between Body Composition and Serum Immunoglobulin Concentrations after Administration of Intravenous Immune Globulin-Preclinical and Clinical Evidence.

The purpose of this study was to investigate the effect of obesity on immunoglobulin G (IgG) pharmacokinetics in a rat model of obesity, and to collect clinical evidence for an association between the body composition and intravenous immune globulin (IVIG) pharmacokinetic parameters in humans. In a preclinical study, pharmacokinetics of human IgG was evaluated after intravenous (IV) and subcutaneous (SC) delivery to obese and lean rats (n = 6 in each group). Serial serum samples were analyzed using an ELISA. The animal body composition was assessed using computer tomography. Patients with primary immunodeficiency currently managed with IVIG, and at a steady state, were enrolled in the clinical study (n = 8). Serum immune globulin (Ig) concentrations were measured at baseline and immediately after the administration of two consecutive treatments, with an additional measurement at two weeks after the first administration. In addition to the patient demographic and clinical characteristics, body composition was measured using bioelectrical impedance analysis. The pharmacokinetics of human IgG was significantly different between the obese and lean rats after both the IV and SC administration of 0.5 g/kg. Furthermore, a significant difference in endogenous rat IgG was observed between the two strains. In the human study, total serum IgG and subtype (IgG1, IgG2, IgG3, IgG4) half-life negatively correlated with the body mass index and fat mass. The mean change in the total serum IgG concentration was significantly correlated to body mass index and fat mass. The results of the studies corroborated one another. In the animal study, most pharmacokinetic parameters of human IgG following IV and SC administration were significantly affected by obesity and changes in the body composition. In the clinical study, the mean serum IgG change after the IVIG administration strongly correlated to the BMI and body fat mass. Future studies are needed to establish the outcomes achieved with more frequent dosing in obese individuals with primary immunodeficiency.

Analysis of lipid composition in muscle tissue of obese and lean rats.

Skeletal muscle is a complex component of the body and muscle contraction has significant implications for caloric expenditure. Lipid metabolism is defined as the production and breakdown of different lipids in the body for metabolic demands. Skeletal muscle plays an important role in lipid metabolism. Obesity and other metabolic diseases are characterized by fatty acid accumulation in the form of triglycerides and cholesterol esters. Furthermore, muscle tissue is vulnerable to lipid composition alterations. Here we used tissue from rats bred for high endurance capacity (HCR) and rats bred for low endurance capacity (LCR). It is well known that HCR rats have better metabolic health than LCR rats, who are more prone to metabolicillnesses. To what extent this arises from differences in lipid composition in the two models is unknown. We used these models to investigate the influence of aerobic fitness on global lipid composition in rat skeletal muscle. The lipids were extracted from the HCR and LCR muscle tissue and characterized using thin layer chromatography to separate and differentiate lipid classes in the rat tissue. We hypothesize that there will be a larger content of free fatty acids, triglycerides, and ceramides in LCR compared to HCR models, potentially contributing to a difference in performance and health of the HCR and LCR rats.

Restoration of mitochondrial Ca2+ and redox homeostasis by enhancement of SK channels rescues Ca2+cycling in HFpEF.

Heart failure is the leading cause of death in the postindustrial world. While many effective therapies are available to treat heart failure with reduced ejection fraction (HFrEF), these approaches fail to improve outcomes in heart failure with preserved ejection fraction (HFpEF). Small conductance Ca2+-activated K+ (SK) channels have recently emerged as an attractive target to improve defective mitochondrial function and reduce emission of damaging reactive oxygen species (ROS) by the organelle. The goal of the present study was to test enhancement of SK as a new strategy to restore abnormal intracellular Ca2+ cycling and mitochondrial redox and Ca2+ homeostasis in ventricular myocytes from HFpEF rat hearts. To achieve this goal as a model of HFpEF we employed ZSF1 obese rats that demonstrate diastolic dysfunction, unchanged fractional shortening and ejection fraction. The confocal Ca2+ and ROS imaging experiments were carried out in ventricular myocytes isolated from lean and obese ZSF1 rats. Mitochondrial matrix [Ca2+] and ROS were assessed in ventricular myocytes expressing matrix-targeted biosensors mtRCamp1h and MLS-HyPer-7, respectively. To increase SK channel activity, we employed adenovirus-mediated overexpression of rat SK channel type 2 and pharmacological SK channel enhancer NS309 . Periodically paced ventricular myocytes isolated from obese ZSF1 rat hearts exhibited enhanced propensity to spontaneous sarcoplasmic reticulum (SR) Ca2+ release, increased mito-ROS production and a dramatic increase in mitochondrial [Ca2+] when exposed to beta-adrenergic agonist isoproterenol. Enhancement of SK channels in ZSF1 obese myocytes prevented mitochondrial Ca2+ overload, reduced mito-ROS emission to the control levels, and improved cytosolic Ca2+ cycling, reducing diastolic SR Ca2+ release. In summary, enhancement of SK channels shows high therapeutic potential in HFpEF by limiting mitochondrial Ca2+ uptake, thereby reducing oxidative stress restraining excessive SR Ca2+ release during diastole.

Feeding Soy Protein Concentrates with Low and High Isoflavones Alters 9 and 18 Weeks Serum Isoflavones and Inflammatory Protein Levels in Lean and Obese Zucker Rats

Soy's anti-inflammatory properties contribute to the health benefits of soy foods. This study was designed to investigate the bioavailability of soy isoflavones and whether the isoflavone content of soy protein concentrate diet would affect serum inflammatory proteins in an obese (fa/fa) Zucker rat model. Six-week-old male lean (L) and obese (O) Zucker rats were fed a casein control diet (C), soy protein concentrate with low isoflavones (SPC-LIF), or soy protein concentrate with high isoflavones (SPC-HIF) (7 rats/dietary group) before being killed at 9 and 18 weeks. Serum samples were analyzed for isoflavones and inflammatory proteins. At both time points, serum total (aglycone + conjugates) genistein, daidzein, and equol concentrations were significantly higher in L-SPC-HIF and O-SPC-HIF groups compared with L-SPC-LIF and O-SPC-LIF groups, respectively, and were not detectable in either L-C or O-C groups. At week 9, serum C-reactive protein (CRP) concentration was significantly lower in O-SPC-HIF group compared with O-C and O-SPC-LIF group, whereas proteins tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels did not differ between any groups. At week 18, serum CRP levels in both O-SPC-HIF and O-SPC-LIF groups were significantly lower compared with the O-C group. TNF-α level was higher in the O-SPC-LIF group compared with both O-C and O-SPC-HIF groups, whereas IL-6 levels were not different between any groups. Taken together, feeding Zucker rats SPC-LIF and SPC-HIF diets led to different serum isoflavone concentrations in both L and O Zucker rats and altered CRP and TNF-α levels in obese Zucker rats compared with controls.

Supplementation with okra combined or not with exercise training is able to protect the heart of animals with metabolic syndrome

The metabolic syndrome (MetS) is a clinical manifestation strongly associated with cardiovascular disease, the main cause of death worldwide. In view of this scenario, many therapeutic proposals have appeared in order to optimize the treatment of individuals with MetS, including the practice of exercise training (ET) and the consumption of okra (O). The aim of the present study was to evaluate the effect of O consumption and/or ET in animals with MetS. In all, 32 male Zucker rats (fa/fa) at 10 weeks old were randomly distributed into four groups of 8 animals each: MetS, MetS+O, MetS+ET and MetS+ET+O, and 8 lean Zucker rats (fa/ +) comprised the control group. Okra was administered by orogastric gavage 2x/day (morning and night, 100 mg/kg), 5 days/week, for 6 weeks. The ET was performed on a treadmill 1x/day (afternoon), 5 days/week, 60 min/day, in an intensity of 70% of maximal capacity, for the same days of O treatment. It was found that, O consumption alone was able to promote improved insulin sensitivity (MetS 93.93 ± 8.54 mg/dL vs. MetS+O 69.95 ± 18.7 mg/dL, p ≤ 0.05, d = 1.65, CI = 50.32 −89.58, triglyceride reduction (MetS 492.9 ± 97.8 mg/dL vs. MetS+O 334.9 ± 98.0 mg/dL, p ≤ 0.05, d = 1.61, CI = 193.2–398.7). In addition, it promoted a reduction in systolic blood pressure (MetS 149.0 ± 9.3 mmHg vs. MetS+O 132.0 ± 11.4 mmHg, p ≤ 0.05, d = 1.63, CI = 120–140), prevented an increase in cardiac collagen (MetS 12.60 ± 2.08% vs. MetS+O 7.52 ± 0.77%, p ≤ 0.05, d = 3.24, CI = 6.56–8.49). When associated with ET, the results were similar. Thus, we conclude that O consumption combined or not with aerobic ET can have a protective effect on the cardiac tissue of rats with MetS.

Application of a novel index for understanding vascular health following pharmacological intervention in a pre-clinical model of metabolic disease.

While a thorough understanding of microvascular function in health and how it becomes compromised with progression of disease risk is critical for developing effective therapeutic interventions, our ability to accurately assess the beneficial impact of pharmacological interventions to improve outcomes is vital. Here we introduce a novel Vascular Health Index (VHI) that allows for simultaneous assessment of changes to vascular reactivity/endothelial function, vascular wall mechanics and microvessel density within cerebral and skeletal muscle vascular networks with progression of metabolic disease in obese Zucker rats (OZR); under control conditions and following pharmacological interventions of clinical relevance. Outcomes are compared to "healthy" conditions in lean Zucker rats. We detail the calculation of vascular health index, full assessments of validity, and describe progressive changes to vascular health index over the development of metabolic disease in obese Zucker rats. Further, we detail the improvement to cerebral and skeletal muscle vascular health index following chronic treatment of obese Zucker rats with anti-hypertensive (15%-52% for skeletal muscle vascular health index; 12%-48% for cerebral vascular health index; p < 0.05 for both), anti-dyslipidemic (13%-48% for skeletal muscle vascular health index; p < 0.05), anti-diabetic (12%-32% for cerebral vascular health index; p < 0.05) and anti-oxidant/inflammation (41%-64% for skeletal muscle vascular health index; 29%-42% for cerebral vascular health index; p < 0.05 for both) drugs. The results present the effectiveness of mechanistically diverse interventions to improve cerebral or skeletal muscle vascular health index in obese Zucker rats and provide insight into the superiority of some pharmacological agents despite similar effectiveness in terms of impact on intended targets. In addition, we demonstrate the utility of including a wider, more integrative approach to the study of microvasculopathy under settings of elevated disease risk and following pharmacological intervention. A major benefit of integrating vascular health index is an increased understanding of the development, timing and efficacy of interventions through greater insight into integrated microvascular function in combination with individual, higher resolution metrics.

Acute effects of a single moderate-intensity exercise bout performed in fast or fed states on cell metabolism and signaling: Comparison between lean and obese rats

AimsAlthough the benefits of exercise can be potentiated by fasting in healthy subjects, few studies evaluated the effects of this intervention on the metabolism of obese subjects. This study investigated the immediate effects of a single moderate-intensity exercise bout performed in fast or fed states on the metabolism of gastrocnemius and soleus of lean and obese rats. Main methodsMale rats received a high-fat diet (HFD) for twelve weeks to induce obesity or were fed standard diet (SD). After this period, the animals were subdivided in groups: fed and rest (FER), fed and exercise (30 min treadmill, FEE), 8 h fasted and rest (FAR) and fasted and exercise (FAE). Muscle samples were used to investigate the oxidative capacity and gene expression of AMPK, PGC1α, SIRT1, HSF1 and HSP70. Key findingsIn relation to lean animals, obese animals' gastrocnemius glycogen decreased 60 %, triglycerides increased 31 %; glucose and alanine oxidation decreased 26 % and 38 %, respectively; in soleus, triglycerides reduced 46 % and glucose oxidation decreased 37 %. Exercise and fasting induced different effects in glycolytic and oxidative muscles of obese rats. In soleus, fasting exercise spared glycogen and increased palmitate oxidation, while in gastrocnemius, glucose oxidation increased. In obese animals' gastrocnemius, AMPK expression decreased 29 % and SIRT1 increased 28 % in relation to lean. The AMPK response was more sensitive to exercise and fasting in lean than obese rats. SignificanceExercise and fasting induced different effects on the metabolism of glycolytic and oxidative muscles of obese rats that can promote health benefits in these animals.

Feeding of Hermetia illucens Larvae Meal Attenuates Hepatic Lipid Synthesis and Fatty Liver Development in Obese Zucker Rats.

The present study tested the hypothesis that dietary insect meal from Hermetia illucens (HI) larvae attenuates the development of liver steatosis and hyperlipidemia in the obese Zucker rat. To test the hypothesis, a 4-week trial with male, obese Zucker rats (n = 30) and male, lean Zucker rats (n = 10) was performed. The obese rats were assigned to three obese groups (group O-C, group O-HI25, group O-HI50) of 10 rats each. The lean rats served as a lean control group (L-C). Group L-C and group O-C were fed a control diet with 20% casein as protein source, whereas 25% and 50% of the protein from casein was replaced with protein from HI larvae meal in the diets of group O-HI25 and O-HI50, respectively. The staining of liver sections with Oil red O revealed an excessive lipid accumulation in the liver of group O-C compared to group L-C, whereas liver lipid accumulation in group O-HI25 and O-HI50 was markedly reduced compared to group O-C. Hepatic concentrations of triglycerides, cholesterol, C14:0, C16:0, C16:1, C18:0, C18:1, the sum of total fatty acids and hepatic mRNA levels of several genes associated with lipid synthesis and plasma concentration of cholesterol were markedly higher in group O-C than in group L-C, but lower in group O-HI50 than in group O-C (p < 0.05). In conclusion, partial replacement of casein by HI larvae meal attenuates liver steatosis and dyslipidemia in obese Zucker rats. This suggests that HI larvae meal serves as a functional food protecting from obesity-induced metabolic disorders.

Can caffeine activate your brown fat? Effects of caffeine, ephedrine, and norepinephrine on nonshivering thermogenesis in congenic lean and obese LA/Ntul//-cp rats

To determine the effects of norepinephrine (NE) or of caffeine (CAF) alone or in combination with ephedrine (EPH) were determined in groups of lean and obese LA/Ntul//-cp Rats, Body weights of obese were &gt;&gt; lean littermates (p=&lt;0.01) and measures of RMR of lean &gt; Obese (p=&lt;0.05). The effects of caffeine, ephedrine, a caffeine+ephedrine combo, and the β- agonist epinephrine was examined. Caffeine (CAF) resulted in a 33% increase in VO2, ‘nonephedrine’ (EPH) a 48% increase, the combination CAF+EPH a 53% increase, and the NE a 33% increase in VO2. In obese rats, the increases in VO2 were of a similar percentage (21 vs 48 vs 47 % vs 31% for CAF, EPH, CAF+EPH and NE respectively although the peak responses attained in the obese tended to be of a significantly lesser absolute magnitude than were observed in the lean phenotype. The time to peak thermogenic response was similar in lean and obese phenotypes for each of the 4 treatment regimens, but the duration of the peak responses to each treatment differed between lean and obese phenotypes (Obese &gt; lean) for CAF, EPH and the CAF+EPH combination but duration of the VO2 response was similar in both phenotypes for the NE treatment. Thus, these observations are consistent with a significant CAF-stimulated thermogenic response that was qualitatively similar to that of NE in both lean and obese phenotypes of the congenic LA/Ntul//-cp rat and which thermogenic responses were further augmented with EPH alone or in combination with CAF. Although the mechanisms of action of the pharmacologic and physiologic mechanisms elicited may differ among the three agents studied the results indicate that they are complimentary in nature in bringing about increases in parameters of nonshivering thermogenesis and thus increasing metabolic energy expenditure in both lean and obese rats. In conclusion, while caffeine as monotherapy may bring about limited weight loss, the combination of caffeine plus ephedrine was more effective in the lean and obese phenotypes of the congenic, non-diabetic LA/Ntul//-cp (Corpulent) rat.

Does the epigenetic expression of obesity, insulin resistance and their metabolic sequelae contribute to brain senescence?

Cognitive senescence and brain shrinkage have been reported in Alzheimer’s disease and is often associated with obesity but the pathophysiologic factors which bring about the neural declines remain unclear. A retrospective examination of factors of Insulin resistance and obesity in lean and obese rats indicated that final body weights of obese phenotype were more than double those of their lean littermates throughout adulthood, and carcass fat content at 10.5 months of age 15-fold greater than similarly fed lean littermates. In addition, the life span of the obese phenotype was decreased by approximately 30% in both male and female rats compared to their lean littermates. In addition, glycemic parameters indicated that the obese rats developed significant insulin resistance, while brain lipid, protein and DNA content were significantly reduced by one third or more in the obese phenotype by ~10 months of age, when they had approached their peak body weights. These observations suggest that the onset and progression obesity and its metabolic sequelae contributes to brain shrinkage, decreased DNA and protein content, key factors in the development of cognitive senescence in aging in this strain of rat.

PS-BPB06-1: GLOMERULAR HEMODYNAMIC CHANGES WITH SGLT2 INHIBITION IN TYPE 2 DIABETIC RATS USING IN VIVO IMAGING

Background and aim: Clinical trials have shown that sodium-glucose co-transporter 2 inhibitor (SGLT2i) not only reduce the risk of heart failure and cardiovascular events in people with type 2 diabetes, but also inhibit DKD progression. Improvement of glomerular hyperfiltration via tubuloglomerular feedback (TGF) is considered to be one of the possible pathways for renal protection with SGLT2i in DKD. However, the mechanisms responsible for kidney protection, especially in the setting of T2D, remain incompletely understood. In previous work, we established a method for measuring single nephron GFR (SNGFR) in mice using in vivo imaging and found that the adenosine/adenosine A1 receptor (A1aR) pathway is central for tubuloglomerular feedback (TGF) signaling and the pathogenesis of glomerular hyperfiltration in animal models of type 1 diabetes (Kidokoro K. et al. Circulation 2019). The mechanism of development of glomerular hyperfiltration, and improvement of glomerular hyperfiltration by SGLT2i may, however, be different in type 1 vs type 2 diabetes and related DKD. However, the detailed regulatory mechanism of GFR have not yet been elucidated in DKD related to T2D. Methods: Zucker lean (ZL) rats and Zucker diabetic fatty (ZDF) rats were used. In the first experiment, SNGFR and diameters of glomerular afferent/efferent arterioles were measured in both groups. Next, we examined the change of SNGFR and diameters of glomerular afferent/efferent arterioles, as well as urinary excretions of glucose and sodium in ZDF after a single-dose administration of SGLT2i (luseogliflozin; 10 mg/kg, gavage) for 120 minutes, which generated the following three groups: SGLT2i group, SGLT2i + adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1 mg/kg) group, and insulin group. Results: SNGFR, afferent and efferent arteriole diameter were significantly increased in ZDF compared to ZL, with greater afferent vs. efferent dilatation. SGLT2i treatment resulted in correction of afferent arteriole vasodilation, with post-SGLT2i diameter that was comparable to baseline levels (p &gt; 0.05). Post-SGLT2i SNGFR was also similar compared to baseline levels. Changes in efferent arteriole diameter were not significant. The inhibitory effect on hyperfiltration by SGLT2i was abolished by the concomitant use of an A1aR antagonist. In contrast, urinary sodium and urinary glucose in SGLT2 inhibitor group increased significantly regardless of adenosine A1 receptor antagonist use. In response to SGLT2i, urinary adenosine and PGE2 increased significantly (p &gt; 0.05), while urine NOx did not change. Conclusion: Regulation of afferent arteriolar tone with SGLT2i is dependent on adenosine/ A1aR signaling an experimental model of T2D related hyperfiltration, regardless of ARB use.

The Epigenetic Expression of Obesity and Its Metabolic Sequelae Contribute to Brain Senescence and Decreased Longevity in Aging Obese LA/Ntul//-cp Rats

Cognitive senescence and brain shrinkage have been reported in Alzheimer’s disease and is often associated with obesity but the pathophysiologic factors which bring about the neural declines remain unclear. A retrospective examination of factors of Insulin resistance and obesity in lean and obese rats indicated that final body weights of obese phenotype were more than double those of their lean littermates throughout adulthood, and carcass fat content at 10.5 months of age 15-fold greater than similarly fed lean littermates. In addition, the life span of the obese phenotype was decreased by approximately 30% in both male and female rats compared to their lean littermates. In addition, glycemic parameters indicated that the obese rats developed significant insulin resistance, while brain lipid, protein and DNA content were significantly reduced by one third or more in the obese phenotype by ~10 months of age, when they had approached their peak body weights. These observations suggest that the onset and progression obesity and its metabolic sequelae contributes to brain shrinkage, decreased DNA and protein content, key factors in the development of cognitive senescence in aging in this strain of rat.

Transcriptomic and proteomic pathways of diabetic and non-diabetic mitochondrial transplantation

Reduced mitochondrial function increases myocardial susceptibility to ischemia–reperfusion injury (IRI) in diabetic hearts. Mitochondrial transplantation (MT) ameliorates IRI, however, the cardioprotective effects of MT may be limited using diabetic mitochondria. Zucker Diabetic Fatty (ZDF) rats were subjected to temporary myocardial RI and then received either vehicle alone or vehicle containing mitochondria isolated from either diabetic ZDF or non-diabetic Zucker lean (ZL) rats. The ZDF rats were allowed to recover for 2 h or 28 days. MT using either ZDF- or ZL-mitochondria provided sustained reduction in infarct size and was associated with overlapping upregulation of pathways associated with muscle contraction, development, organization, and anti-apoptosis. MT using either ZDF- or ZL-mitochondria also significantly preserved myocardial function, however, ZL- mitochondria provided a more robust long-term preservation of myocardial function through the mitochondria dependent upregulation of pathways for cardiac and muscle metabolism and development. MT using either diabetic or non-diabetic mitochondria decreased infarct size and preserved functional recovery, however, the cardioprotection afforded by MT was attenuated in hearts receiving diabetic compared to non-diabetic MT.

Urine trace element disorder along with renal function injury in vitamin D deficient diabetic rats and intervention effect of 1α,25-dihydroxyvitamin D3.

Trace element metabolism disorders are often secondary to disorders of glucose metabolism in diabetes. Although 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] could ameliorate abnormal glucose metabolism in the development of diabetes, the effect on trace element metabolism is unclear. The objective of this study was to evaluate the influence of 1,25(OH)2D3 on urinary excretions of trace elements in Zucker diabetic fatty (ZDF) rats. At 6 weeks of age, male ZDF (n = 40) rats were subdivided into four groups: diabetic model (ZDF), low-dose (ZDF + VL, 2 μg/kg⋅bw), middle-dose (ZDF + VM, 8 μg/kg⋅bw) and high-dose (ZDF + VH, 16 μg/kg⋅bw) 1,25(OH)2D3 groups. Another 10 Zucker lean (ZL) rats served as a control group. All rats were given vitamin D deficient Purina #5008 chow and the intervention groups were given the corresponding dose of 1,25(OH)2D3 by gavage on alternate days for 7 weeks. Microalbuminuria (MALB) and urinary creatinine concentration were detected by a biochemical autoanalyzer. Urine trace element concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS) and were corrected by urinary creatinine. Throughout the intervention phase, MALB, UACR and urinary creatinine levels in the ZDF group were significantly higher than those in the ZL group, and showed a gradual increase with the prolongation of the intervention time. These changes were reversed in a dose-dependent manner after 1,25(OH)2D3 intervention (P < 0.05). Correspondingly, most of the urinary trace element excretions in the ZDF rats were significantly increased compared with the ZL group, and 1,25(OH)2D3 intervention significantly reduced the urinary copper (Cu), zinc (Zn), selenium (Se) and molybdenum (Mo) levels in the ZDF rats (P < 0.05), especially in the medium and high dose groups. 1,25(OH)2D3 had improvement effects on urinary Cu, Zn, Se, and Mo excretions in ZDF rats, suggesting that it may be related to the reduction of diabetic renal impairment and renal oxidative damage.