Fat Depot Weights Research Articles

Obesity Human Soluble Prorenin Receptor Expressed in Adipose Tissue Improves Insulin Sensitivity and Endothelial Function in Obese Female Mice.

Soluble prorenin receptor (sPRR) is a component of the renin-angiotensin system (RAS) identified as a plasma biomarker for human metabolic disease. However, what tissue source of sPRR is implicated in the modulation of metabolic function remains unclear. This study investigated the contribution of human sPRR (HsPRR) produced in the adipose tissue (Adi) on the metabolic and cardiovascular function of lean and obese male and female mice. Adi-HsPRR mice, generated by crossing human sPRR-Myc-tag and Adiponectin/Cre mice, were fed a low-fat or high-fat diet (10% and 60% kCal from fat, respectively) for 20 weeks. Obese Adi-HsPRR mice showed elevated sPRR levels in adipose tissue without affecting adipocyte size or fat depot weight. Despite plasma sPRR being similar between obese Adi-HsPRR and control female mice, a positive correlation between plasma sPRR and adiposity was present only in controls. Obese Adi-HsPRR male mice showed elevated plasma sPRR compared with controls, but no correlation with adiposity was found in either group. Nevertheless, Adi-HsPRR expression improved insulin sensitivity and endothelial function, reduced adipogenic genes mRNA abundance (PPARg, SEBP1C and CD36), and increased plasma Angiotensin 1-7 levels only in obese HsPPR female mice. Taken together, elevated HsPRR in adipose tissue improved metabolic and vascular function in obese female mice despite normal circulating levels of sPRR, whereas increased local and circulating levels of HsPRR did not influence metabolic and cardiovascular function in obese male mice. Our data suggest that increased plasma sPRR associated with metabolic disease could be produced by other tissues rather than adipocytes.

THU297 Metformin Treatment Of Juvenile Mice Alters Aging-Related Developmental And Metabolic Phenotypes In Sex-Dependent And -Independent Manners

Abstract Disclosure: Y. Zhu: None. M. Engmann: None. D. Medina: None. A. Bartke: None. B.S. Ellsworth: None. R. Yuan: None. Metformin is a widely used drug for the treatment of type 2 diabetes that also has a strong potential for long-term effects which may extend healthspan and longevity. In the current study, C57BL/6J (B6) juvenile female and male mice were treated with metformin between the ages of 15 and 56 days. Saline was used as the control. The results show that early-life treatment with metformin has profound effects on developmental and metabolic traits. Body weight was significantly reduced by metformin treatment in both sexes (P<0.05, t test). At 10 weeks of age, mice were euthanized, and organ weights were recorded. In treated males, weights of epididymal, perirenal, and brown fat depots were significantly reduced (P<0.05, t test). Pancreas weight was significantly reduced in both sexes (P<0.05, t test). Hypothalamus weight was significantly reduced in the females, and whole brain weight was significantly reduced in the males. Tail length as well as age of sexual maturation were not significantly altered in either sex. No significant difference was found in circulating insulin-like growth factor 1 (IGF1) or adiponectin. Circulating insulin was significantly reduced by the treatment under fasting and non-fasting conditions in the male mice, while in the females no significant difference was detected. Insulin sensitivity, calculated by the quantitative insulin-sensitivity check index (QUICKI), was suggestively increased in the male mice (P=0.062, t test). Glucose tolerance test (GTT) did not show a significant difference in treated female mice; however, comparing the area under curve, metformin treatment significantly improved the glucose tolerance of male mice (P=0.014, t test). Insulin tolerance test (ITT) showed no significant difference in the male mice; but, unexpectedly, in female mice, metformin treatment significantly reduced insulin sensitivity. This study revealed that early-life metformin treatment alters development and metabolism of mice in both sex-specific and non-specific manners, which may have long-term impacts on metabolism in aging. Interestingly, comparing the results of this study with previous studies of metformin-treated heterogenous UM-HET3 mice, further analyses revealed that metformin effects on body weight, age of sexual maturation, body size, IGF1, adiponectin, insulin, GTT, and ITT, are genetically dependent. Funding: SIU collaborative grant to Rong Yuan and Buffy S. Ellsworth. SIU Geriatric foundation by Andrzej Bartke Presentation: Thursday, June 15, 2023

Cleft palate and minor metabolic disturbances in a mouse global Arl15 gene knockout.

ARL15, a small GTPase protein, was linked to metabolic traits in association studies. We aimed to test the Arl15 gene as a functional candidate for metabolic traits in the mouse. CRISPR/Cas9 germline knockout (KO) of Arl15 showed that homozygotes were postnatal lethal and exhibited a complete cleft palate (CP). Also, decreased cell migration was observed from Arl15 KO mouse embryonic fibroblasts (MEFs). Metabolic phenotyping of heterozygotes showed that females had reduced fat mass on a chow diet from 14 weeks of age. Mild body composition phenotypes were also observed in heterozygous mice on a high-fat diet (HFD)/low-fat diet (LFD). Females on a HFD showed reduced body weight, gonadal fat depot weight and brown adipose tissue (BAT) weight. In contrast, in the LFD group, females showed increased bone mineral density (BMD), while males showed a trend toward reduced BMD. Clinical biochemistry analysis of plasma on HFD showed transient lower adiponectin at 20 weeks of age in females. Urinary and plasma Mg2+ concentrations were not significantly different. Our phenotyping data showed that Arl15 is essential for craniofacial development. Adult metabolic phenotyping revealed potential roles in brown adipose tissue and bone development.

Dietary Oil Type and Late Feed Restriction Elicit Synergistic Effects on Growth, Caeca Bacteria, Carcass, Fat Accretion, and Muscle Lipids in Female Broilers

AbstractThe influence of dietary oil type (OT) and late feed restriction (FR) on growth, caeca bacteria count, carcass, separable fat depots, serum and muscle lipids, and meat quality in broilers is examined. In total, 224, 21‐day‐old female Arbor acres broilers are randomly allotted to either PN, Unrestricted+50 g kg−1 palm oil (PO); PR, 25%‐FR+PO; SN, Unrestricted+50 g kg−1 soybean oil (SO); or SR, 25%‐FR+SO for 21 d. The SN and PR birds have the heaviest and lightest body weight gain (BWG), respectively. Feed conversion ratio (FCR) is poorer in the PN birds. Feed‐restricted birds have more caeca Lactobacillus and lower Salmonella, serum cholesterol, and triglycerides. Carcass yield is higher in SR birds and lower in PN birds. The FR‐OT interaction is significant for muscle lipids and weight of fat depots. The PN birds deposit more abdominal, intramuscular, sartorial, mesentery and neck fats, muscle saturated fatty acids, and C18:1n‐9 and lower C18:3n‐3 and C20:5n‐3 than other birds. Neither OT nor FR affects the pH, color, water holding capacity, and oxidative stability of breast meat. The changes elicited by 25%‐FR on BWG, FCR, carcass yield, depot fats, and muscle lipids in female broilers are dependent on dietary OT.Practical Application: Fast growth rate and unrestricted access to feed can predispose broiler chickens to excessive fat accretion, which is counterproductive. Producing high‐quality carcasses that meet consumers’ expectation is crucial for sustainable and efficient broiler production. The possible interaction between dietary OT and late quantitative FR in mitigating excessive fat accretion and altering production indices in female broilers is explored. Late quantitative FR reduces BWG, FCR, serum lipids, caeca pH and Salmonella spp. and fat accretion in fat depots, and enhances carcass yield and caeca Lactobacillus spp. However, the impacts are more pronounced in the PO birds than the SO birds. Late FR improves the C18:3n‐3 and C18:2n‐6 contents in PO meat while reducing the C14:0 and C16:0 contents in SO meat. These findings explicate that dietary OT and late quantitative FR can be synergistically used to mitigate excessive fat accretion and alter growth, caeca microflora, and muscle lipids in broilers.

Oral Supplementation with the Polyamine Spermidine Affects Hepatic but Not Pulmonary Lipid Metabolism in Lean but Not Obese Mice.

The polyamine spermidine is discussed as a caloric restriction mimetic and therapeutic option for obesity and related comorbidities. This study tested oral spermidine supplementation with regard to the systemic, hepatic and pulmonary lipid metabolism under different diet conditions. Male C57BL/6 mice were fed a purified control (CD), high sucrose (HSD) or high fat (HFD) diet with (-S) or without spermidine for 30 weeks. In CD-fed mice, spermidine decreased body and adipose tissue weights and reduced hepatic lipid content. The HSD induced hepatic lipid synthesis and accumulation and hypercholesterolemia. This was not affected by spermidine supplementation, but body weight and blood glucose were lower in HSD-S compared to HSD. HFD-fed mice showed higher body and fat depot weights, prediabetes, hypercholesterolemia and severe liver steatosis, which were not altered by spermidine. Within the liver, spermidine diminished hepatic expression of lipogenic transcription factors SREBF1 and 2 under HSD and HFD and affected the expression of other lipid-related enzymes. In contrast, diet and spermidine exerted only minor effects on pulmonary parameters. Thus, oral spermidine supplementation affects lipid metabolism in a diet-dependent manner, with significant reductions in body fat and weight under physiological nutrition and positive effects on weight and blood glucose under high sucrose intake, but no impact on dietary fat-related parameters.

Mitochondrial Uncoupler BAM15 Ameliorates Associated Metabolic PCOS Traits in a Hyperandrogenic PCOS Mouse Model

Background: Polycystic ovary syndrome (PCOS) is a common endocrine condition characterized by endocrine, reproductive and metabolic abnormalities. There is no cure for PCOS and existing treatments are suboptimal. Obesity and adverse metabolic features are prevalent in PCOS patients, but weight loss has a beneficial effect on PCOS features. However, dietary interventions aimed at weight loss are difficult to sustain long-term. Interestingly, recent data from animal studies has shown that a mitochondrial uncoupler, BAM15, is an effective approach to pharmacologically treat obesity and metabolic diseases. Aim: To investigate the efficacy of BAM15 to ameliorate PCOS-traits in a PCOS mouse model. Method: The effect of BAM15 treatment on metabolic and reproductive PCOS features were evaluated in dihydrotestosterone (DHT)-induced PCOS mice fed a standard chow diet ± BAM15 for 10 weeks. Results: As expected, exposure of female mice to DHT induced the PCOS metabolic features of increased body weight (P<0.05), lean mass (P<0.001), increased parametrial and mesenteric fat pad weights (P<0.05) and adipocyte hypertrophy (P<0.05). DHT-induced PCOS mice also exhibited increased HOMA-IR, cholesterol and fasting triglyceride levels and hepatic steatosis (all P<0.05). Conversely, DHT-induced PCOS females treated with BAM15 displayed lowered body weights similar with controls, a significant decrease in parametrial and mesenteric fat depot weights (P<0.05) and reduced adipocyte hypertrophy. Likewise, BAM15 treatment decreased HOMA-IR, cholesterol and fasting triglyceride levels and the degree of hepatic steatosis observed in PCOS females, to levels comparable with control females. Lastly, PCOS mice presented the reproductive PCOS traits of irregular cycles and ovulatory dysfunction, though BAM15 treatment did not improve these PCOS features. Conclusion: These findings demonstrate that the pharmacologic mitochondrial uncoupler BAM15 is able to ameliorate metabolic PCOS features in a PCOS mouse model. These data provide evidence to support BAM15 as a potential innovative therapeutic approach to manage associated metabolic PCOS features.

Beneficial Effects of Empagliflozin Are Mediated by Reduced Renal Inflammation and Oxidative Stress in Spontaneously Hypertensive Rats Expressing Human C-Reactive Protein.

Gliflozins (inhibitors of sodium-glucose cotransporter 2) show many beneficial actions beyond their antidiabetic effects. The underlying mechanisms of these additional protective effects are still not well understood, especially under non-diabetic conditions. Therefore, we analyzed the effects of empagliflozin in young (3-month-old) and adult (12-month-old) male spontaneously hypertensive rats (SHR) expressing human C-reactive protein (CRP) in the liver. SHR-CRP rats are a non-diabetic model of metabolic syndrome, inflammation, and organ damage. Empagliflozin was given in a daily dose of 10 mg/kg body weight for 8 weeks. Both age groups of SHR-CRP rats treated with empagliflozin had lower body weight, decreased weight of fat depots, reduced ectopic fat accumulation in the liver and kidneys, and decreased levels of plasma insulin and β-hydroxybutyrate. Empagliflozin effectively reduced ectopic renal fat accumulation, and was associated with decreased inflammation. Exclusively in young rats, decreased microalbuminuria after empagliflozin treatment was accompanied by attenuated oxidative stress. In adult animals, empagliflozin also improved left ventricle function. In conclusion, in young animals, the beneficial renoprotective effects of empagliflozin could be ascribed to reduced lipid deposition in the kidney and the attenuation of oxidative stress and inflammation. In contrast, hepatic lipid metabolism was ameliorated in adult rats.

Deficiency of mature B cells does not alter the atherogenic response to castration in male mice

Testosterone deficiency in men is associated with increased atherosclerosis burden and increased cardiovascular risk. In male mice, testosterone deficiency induced by castration increases atherosclerosis as well as mature B cell numbers in spleen. As B cells are potentially pro-atherogenic, we hypothesized that there may be a link between these effects. To address whether mature B cell deficiency alter the atherogenic response to castration, we studied B cell-deficient μMT and genotype control male mice on an atherosclerosis-prone Apoe−/− background that were castrated or sham-operated pre-pubertally and fed a high-fat diet between 8 and 16 weeks of age to accelerate atherosclerosis development. Genotype did not affect the effects of castration on body weight or weights of fat depots and there were no differences in serum cholesterol levels across the four groups. Atherosclerosis assessed by quantification of lesion area in serial sections of the aortic root was significantly increased by castration and by the μMT mutation, with no significant interaction between genotype and surgery. In conclusion, castration evokes a similar atherogenic response in B cell-deficient μMT and control mice. These data suggest that atherogenesis following castration is unrelated to the effects of androgens on mature B cell numbers.

The Effect of High-Intensity Interval Training on the Adiponectin and TNF-α Levels of Serum and Adipose Tissues in Rats Fed with a High-Fat Diet Plus Sucrose Solution

Background: Adipocytokines secreted by adipose tissue are suggested to play a significant role in developing obesity-related complications. On the other hand, regular high-intensity interval training (HIIT) has been shown to reduce the risk of metabolic complications in obese subjects. Objectives: The effect of HIIT was evaluated on serum and adipose tissues (inguinal and retroperitoneal) adiponectin and TNF-α levels in rats fed with a high-fat diet plus sucrose solution (HFDS). Methods: Thirty-two male Wistar rats were randomly divided into HFDS and standard diet (SD) groups. After 12 weeks, each group was divided into a sedentary group and a HIIT group. An HIIT program was performed three times/week for eight weeks. Inguinal and retroperitoneal adipose tissues and serum were collected to assay adiponectin and TNF-α levels. Also, serum glucose and insulin levels, insulin resistance index (HOMA-IR) were measured. Results: HFDS significantly increased weight gain, weight of inguinal (P = 0.001) and retroperitoneal fat depots (P < 0.001), and HOMA-IR (P < 0.001) but reduced serum TNF-α levels (P = 0.011). HIIT was able to decrease weight gain and fat mass (P < 0.05) but did not affect inguinal and retroperitoneal fat depots’ adipokines (adiponectin and TNF-α) levels and HOMA-IR (P > 0.05). Conclusions: HIIT program can have significant reducing effects on weight gain and fat weights, but it does not effect on circulating and fat depots' adiponectin and TNF-α levels in rats fed a HFDS.

The effect of high-intensity interval training on serum and adipose tissues vaspin levels in rats fed a high-fat high-sucrose diet.

Vaspin is an adipocytokine with insulin-sensitizing and anti-inflammatory traits. The purpose of this study was to evaluate the effect of high-intensity interval training (HIIT) on serum, visceral and subcutaneous adipose tissue vaspin levels in rats exposed to a diet high in fat and sugar (HFS). Thirty-two male Wistar rats were randomly divided into HFS and standard diet (SD) groups. After 12weeks, each group was divided into sedentary and HIIT groups. HIIT program was performed 3times/week for 8weeks. Retroperitoneal adipose tissue, inguinal adipose tissue and serum were collected to analyze vaspin levels. Also, serum glucose and insulin levels, insulin resistance index (HOMA-IR) and retroperitoneal and inguinal fat weights were measured. HFS significantly increased weight gain, weight of inguinal (p=0.001) and retroperitoneal fat depots (p<0.001), serum glucose levels (p<0.001) and HOMA-IR (p<0.001). The HIIT was able to decline weight gain and fat mass (p<0.05) but did not affect inguinal and retroperitoneal fat depots' vaspin levels. Eight weeks' HIIT significantly increased serum vaspin (p=0.002) and decreased insulin (p=0.001) levels only in rats fed with SD. Although the HIIT program can cause significantly reducing effects on weight gain and fat depots' weights, it does not effect on circulating and fat depots' vaspin levels in rats fed an HFS.

Modulation of the dynamics and cellularity of adipose tissues in different fat depots in broilers by dietary dexamethasone.

The objective of this investigation was to determine the effects of dexamethasone (DEX) on the weight and cellularity of abdominal and subcutaneous fat depots. The study was conducted on four broiler chicks (20 chicks per group) fed commercial feed and water ad libitum. The DEX was supplied with feed at 0 mg/kg (non-DEX), 3 mg/kg (DEX-1), 5 mg/kg (DEX-2), and 7 mg/kg (DEX-3) from day 0 to day 28. The entire abdominal and subcutaneous fat depots were collected and weighed after sacrificing five birds from each group on days 14 and 28. The DEX groups had considerably lower (p < 0.05) fat depot weights with dose-related variation noted among the DEX groups. The histological findings revealed the presence of unilocular, round to oval-shaped adipocytes. The DEX-1 and DEX-2 had way lower (p < 0.05) numbers of adipocytes while the DEX-3 had considerably higher (p < 0.05) numbers of adipocytes than the non-DEX. DEX-1 and DEX-2 had larger (p < 0.05) adipocytes whereas DEX-3 had smaller adipocytes than the non-DEX. Adipocyte sizes and fat depot weights were found to have very strong negative relationships. Dietary DEX affects the growth and distribution of abdominal and subcutaneous fat depots and adipocyte cellularity subjected to both dose and duration of DEX treatment.

PHYTOPHARMACOLOGICAL EVALUATION OF HYDROALCOHOLIC EXTRACT OF BARK OF PONGAMIA GLABRA VENT. FOR ANTI-OBESITY ACTIVITY AND EFFECT ON LIPID PROFILE AND HEPATIC ENZYMES

Pongamia glabra is a native Indian subcontinent as well as south-east Asia drug used widely in many herbal formulations. The bark extract is used in the present study to evaluate its anti-obesity activity and its effect on lipid profile and hepatic enzyme. In-vivo studies were done using high fat diet along with DPMA model. Anti-obesity Evaluations included in the study was analysis of serum biochemical parameters (Serum Lipid Profile), determination of atherogenic index and coronary risk, Determination of Adiposity Levels, Fat Depot and Liver weight/Body weight Ratio (%) and histopathological analysis of liver tissues and adipose tissues. The results of the present study suggested that in actute toxicity studies, animals did not show any mortality at the dose of 500 mg/kg;bw. The Pongamia glabra bark at the dose of 500 mg/kg body weight found to show strong reducing effect on serum TC, TG and LDL levels among the treatments. The atherogenic index and coronary risk index showed significant reduction when treated with hydroalcoholic extract of Pongamia glabra bark extract. A significant increase in Lee index was observed in rat fed with high fat dies. The study showed that Weight of different body fat depots i.e. epitdidymal, retroperitoneal, mesenteric fat depot and total fat were significantly increased in HFD group as compared to the normal control group of rat. The histopathological studies suggested that Pongamia glabra bark extracts suppress the enlargement of hepatocytes and the accumulation of vesicles in the hepatic tissues. The present study thus clearly indicates that Pongamia glabra stem bark has a significant anti-obesity effect which supports its traditional uses.

High cysteine diet reduces insulin resistance in SHR-CRP rats.

Increased plasma total cysteine (tCys) has been associated with obesity and metabolic syndrome in human and some animal studies but the underlying mechanisms remain unclear. In this study, we aimed at evaluating the effects of high cysteine diet administered to SHR-CRP transgenic rats, a model of metabolic syndrome and inflammation. SHR-CRP rats were fed either standard (3.2 g cystine/kg diet) or high cysteine diet (HCD, enriched with additional 4 g L-cysteine/kg diet). After 4 weeks, urine, plasma and tissue samples were collected and parameters of metabolic syndrome, sulfur metabolites and hepatic gene expression were evaluated. Rats on HCD exhibited similar body weights and weights of fat depots, reduced levels of serum insulin, and reduced oxidative stress in the liver. The HCD did not change concentrations of tCys in tissues and body fluids while taurine in tissues and body fluids, and urinary sulfate were significantly increased. In contrast, betaine levels were significantly reduced possibly compensating for taurine elevation. In summary, increased Cys intake did not induce obesity while it ameliorated insulin resistance in the SHR-CRP rats, possibly due to beneficial effects of accumulating taurine.

PSVI-23 Depot- specific patterns of mRNA and miRNA gene expression in adipose tissue from Texel-cross and Suffolk lambs

Abstract Excess fat deposition is costly to the producer in terms of input and final product; it also usually does not occur equally across all adipose depots. Further examination is necessary to determine a correlation between varying gene expression and fatty acid composition in different tissue depots, and further, across different breeds. Texel-Suffolk (n = 5) and Suffolk-Suffolk (n = 4) lambs were finished to 203 d of age and used to compare both mRNA and microRNA (miR) gene expression changes between breed and among tissue depots. Seven different depots were harvested and snap-frozen from all nine lambs. The liver, longissimus muscle of the rib, kidney fat, mesenteric fat, omental fat, subcutaneous fat, and intermuscular fat were all harvested. Texel-sired lambs had greater (P &amp;lt; 0.05) flank streaking, quality grade, and weight of fat depots compared to Suffolk. Texel-cross lambs had higher (P &amp;lt; 0.05) oleic-to-stearic fatty acid ratio than Suffolk lambs in this study, displaying a breed difference concerning this desaturation ratio. Tissue and breed interactions were observed for oleic-to-stearic and palmitoleic-to-palmitic ratio differences (P &amp;lt; 0.05) depending on tissue type. Tissue and breed interactions were trending in various tissues concerning the expression of the gene, stearoyl-CoA desaturase-1(SCD-1). SCD-1 seemed to be upregulated (P &amp;lt; 0.10) in a multitude of tissues while others do not appear to be differentially expressed, dependent upon breed. Data showed an association between SCD-1 and mi-199a-3p among different tissue variations. This may suggest that adipose tissue is more complex than what is currently known. Lipogenic gene expression differed between tissue and adipose depots, and could potentially broaden targets that could aid in maximizing animal efficiency.

A novel PCOS rat model and an evaluation of its reproductive, metabolic, and behavioral phenotypes.

BackgroundAlthough animal models of PCOS have been used in many studies, none of them can reproduce both the reproductive and metabolic phenotypes of PCOS. In addition, behavioral parameters have not been evaluated in PCOS animal models.PurposeWe tried to produce an improved rat model of PCOS, and the reproductive, metabolic, and behavioral phenotypes of the model rats were evaluated.MethodsFemale rats were implanted with silicon tubes containing oil‐dissolved dihydrotestosterone (Oil‐DHT) as a new PCOS model. Their phenotypes were compared with those of conventional PCOS model rats (DHT), into which tubes containing crystalline DHT were implanted, and non‐DHT‐treated rats (control).ResultsBoth the Oil‐DHT and DHT rats showed greater body weight gain, food intake, and fat depot weight than the control rats. Furthermore, these groups showed fewer estrous stages and increased numbers of cystic follicles. The DHT rats exhibited lower ovarian and uterine weights than the control rats, whereas no such changes were observed in the Oil‐DHT rats. The Oil‐DHT and DHT rats showed less locomotor activity in the light phase than the control rats.ConclusionsOur proposed PCOS model reproduced both the reproductive and metabolic phenotypes of PCOS and may have potential for PCOS research.

Nicotinamide riboside has minimal impact on energy metabolism in mouse models of mild obesity.

Supplementation with precursors of NAD has been shown to prevent and reverse insulin resistance, mitochondrial dysfunction, and liver damage in mouse models of diet-induced obesity. We asked whether the beneficial effects of supplementation with the NAD precursor nicotinamide riboside (NR) are dependent on mouse strain. We compared the effects of NR supplementation on whole-body energy metabolism and mitochondrial function in mildly obese C57BL/6N and C57BL/6J mice, two commonly used strains to investigate metabolism. Male C57BL/6N and C57BL/6J mice were fed a high-fat diet (HFD) or standard chow with or without NR supplementation for 8 weeks. Body and organ weights, glucose tolerance, and metabolic parameters as well as mitochondrial O2 flux in liver and muscle fibers were assessed. We found that NR supplementation had no influence on body or organ weight, glucose metabolism or hepatic lipid accumulation, energy expenditure, or metabolic flexibility but increased mitochondrial respiration in soleus muscle in both mouse strains. Strain-dependent differences were detected for body and fat depot weight, fasting blood glucose, hepatic lipid accumulation, and energy expenditure. We conclude that, in mild obesity, NR supplementation does not alter metabolic phenotype in two commonly used laboratory mouse strains.

Metabolic PCOS Features Are Ameliorated by Mitochondrial Uncoupler BAM15 in a PCOS Mouse Model

Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterized by endocrine, reproductive and metabolic dysfunction. At present, there is no cure for PCOS and current treatments are suboptimal. Obesity and adverse metabolic features are prevalent in women with PCOS, with weight loss having a beneficial effect on PCOS features. The use of dietary interventions aimed at weight loss have low long-term compliance in women suffering from PCOS. Recent data from animal studies has shown that a small molecule mitochondrial uncoupler, BAM15, is an effective method to pharmacologically treat obesity and metabolic diseases. Therefore, the aim of this study was to investigate the efficacy of BAM15 to ameliorate PCOS-traits in a hyperandrogenic PCOS mouse model. As expected, exposure of female mice to dihydrotestosterone (DHT) induced the PCOS metabolic features of increased body weight (P<0.05), lean mass (P<0.001), increased parametrial and mesenteric fat pad weights (both P<0.05) and adipocyte hypertrophy (P<0.05). Additionally, DHT-induced PCOS mice exhibited insulin resistance measured by HOMA-IR, increased cholesterol and fasting triglyceride levels and hepatic steatosis (all P<0.05). In contrast, DHT-induced PCOS females treated with BAM15 displayed body weights which were comparable with controls, a significant decrease in parametrial and mesenteric fat depot weights (P<0.05) and reduced adipocyte hypertrophy. Furthermore, BAM15 treatment decreased insulin resistance, cholesterol and fasting triglyceride levels, as well as the degree of hepatic steatosis observed in PCOS females, to levels comparable with controls. PCOS mice presented the reproductive PCOS traits of irregular cycles and ovulatory dysfunction, however BAM15 did not improve these PCOS traits. These findings demonstrate that the pharmacologic mitochondrial uncoupler BAM15 is able to ameliorate metabolic PCOS features in a hyperandrogenic PCOS mouse model. These data provide compelling evidence to support BAM15 as a potential innovative and viable therapeutic approach to manage metabolic traits associated with PCOS.

Impact of sex on the adaptation of adult mice to long consumption of sweet-fat diet.

In rodents, the most adequate model of human diet-induced obesity is obesity caused by the consumption of a sweet-fat diet (SFD), which causes more pronounced adiposity in females than in males. The aim of this work was to determine the sex-associated effect of SFD on the expression of genes related to carbohydrate-lipid metabolism in adult mice. For 10 weeks, male and female С57Bl mice were fed a standard laboratory chow (Control group) or a diet, which consisted of laboratory chow supplemented with sweet cookies, sunflower seeds and lard (SFD group). Weights of body, liver and fat depots, blood concentrations of hormones and metabolites, liver fat, and mRNA levels of genes involved in regulation of energy metabolism in the liver, perigonadal and subcutaneous white adipose tissue (pgWAT, scWAT) and brown adipose tissue (BAT) were measured. SFD increased body weight and insulin resistance in mice of both sexes. Female mice that consumed SFD (SFD females) had a greater increase in adiposity than SFD males. SFD females showed a decreased expression of genes related to lipogenesis (Lpl) and glucose metabolism (G6pc, Pklr) in liver, as well as lipogenesis (Lpl, Slca4) and lipolysis (Lipe) in pgWAT, suggesting reduced energy expenditure. In contrast, SFD males showed increased lean mass gain, plasma insulin and FGF21 levels, expressions of Cpt1α gene in pgWAT and scWAT and Pklr gene in liver, suggesting enhanced lipid and glucose oxidation in these organs. Thus, in mice, there are sex-dependent differences in adaptation to SFD at the transcriptional level, which can help to explain higher adiposity in females under SFD consumtion.

SUN-591 PAPP-A Inhibition - a Novel Anti-Obesity Therapeutic Approach

Background: Adipose tissue is a heterogeneous endocrine organ with tremendous capability for expansion. The antithetical pathogenicity of visceral adipose tissue (VAT), compared to subcutaneous adipose tissue (SAT), has been linked to the metabolic stress of enlarging mature adipocytes and a limited ability to recruit new adipocytes. One of the major distinguishing features of VAT preadipocytes is the high expression of Pregnancy Associated Plasma Protein–A (PAPP-A) when compared to SAT. PAPP-A is a zinc metalloprotease that is secreted, and can associate with the cell surface in an autocrine or paracrine fashion. It is the only known physiological IGFBP-4 (Insulin-like Growth Factor Binding Protein) protease. It cleaves the IGF/IGFBP-4 complex, releasing IGF, making it more bio-available for receptor engagement and downstream signaling. The role of IGFs in adipogenic differentiation is well established. While there is quantitative depot-specific variability in PAPP-A expression among preadipocytes, mature adipocytes do not express any PAPP-A. These findings suggest that there may be a relationship between PAPP-A inhibition and adipogenic differentiation and maturation. Similar to human VAT, PAPP-A expression is highest in visceral fat in murine models. The PAPP-A KO mice, when fed a high fat diet, showed restrained visceral adiposity and decreased visceral adipocyte size, suggesting that PAPP-A could regulate adipogenesis locally in tissues that express high PAPP-A. Hypothesis: PAPP-A inhibition is a novel anti-obesity treatment strategy. Methods/Results: We fed 20 male and 20 female wild type mice 42% high fat diet (HFD) starting at 10 weeks of age. Concomitantly, we treated 10 mice in each group with either mAb-PA1/41 (a PAPP-A neutralizing monoclonal antibody) or IgG2a (control isotope), intraperitoneally at a dose of 30 mg/kg weekly for the duration of the HFD. At the end of 15 weeks, the mice were sacrificed and the adipose tissue, serum and solid organs were harvested.Compared to the control (IgG2a) mice, the mAb-PA1/41 treated male and female mice gained 40% less weight (P = 0.03) and had smaller visceral fat depots (mesenteric and pericardial). Also, when we looked at individual adipocyte size, the drug treated mice had 45% smaller mesenteric adipocytes (P = 0.002) and 44% smaller pericardial adipocytes (P= 0.003). Also, the visceral depots in the drug treated mice had 30% more cells (P = 0.006). In both groups, there was decreased liver lipid content (P=0.005). The mAb-PA1/41 treatment had no significant effect on subcutaneous fat depots. Conclusion: Pharmacologic inhibition of PAPP-A decreased weight gain, visceral fat depot weight, visceral adipocyte size, hepatic lipid deposition and increased visceral adipocyte cell number in both male and female mice that were fed a high fat diet.

Vitamin D Promotes Adiposity But Improves Associated Metabolic Derangements In An Obese Rat Model

Abstract Background Obesity is a worldwide problem and is a major risk factor for chronic diseases. The relation between obesity and vitamin D is not completely understood. Obesity is associated with vitamin D insufficiency. Some studies claim that vitamin D may reduce lipogenesis and others claim that vitamin D can promote adipogenesis. Aim of the study This study was planned to evaluate the effect of alteration in vitamin D level on body weight and adipose tissue metabolism in an obese rat model. Methods 32 Female Albino-rats were randomly allocated into: control group (C, n = 8), fed on control diet containing 1000 IU vitamin D/kg diet, and a high caloric diet group (HCD, n = 32). The HCD group was further subdivided into 3 groups according to the vitamin D dose into: standard vitamin D dose group (HCD+SVD) containing 1000 IU vitamin D/kg diet, low vitamin D dose group (HCD+LVD) containing 25 IU vitamin D/kg diet and high vitamin D dose group (HCD+HVD) containing 5169 IU vitamin D/kg diet. Body mass index, serum vitamin D, glucose, lipid profile, TNF-α and adipose tissue UCP-1 were measured. Different fat depots were weighed and histopathologically assessed. Results HCD+HVD group showed a significant increase in the final body mass index and in the different fat depot weights compared to all groups. Compared to the HCD+SVD group, the HCD+HVD group showed significantly lower serum total cholesterol and LDL-c levels, while it showed a non-significant change in serum glucose, TNF-α and visceral adipose tissue UCP-1. A significant negative correlation was found between serum 25(OH)D and visceral adipose tissue UCP-1. HCD+LVD showed the highest visceral adipose tissue UCP-1 compared to all groups. Conclusion Vitamin D promoted adiposity and decreased visceral adipose tissue UCP-1 but improved the associated derangements in lipid profile.