Perirenal Depots Research Articles

Obesity exacerbates ischemia-reperfusion injury and senescence in murine kidneys and perirenal adipose tissues.

Obesity is a major worldwide health problem and can be related to cellular senescence. Along with the rise in obesity, the comorbidity of renal ischemia-reperfusion (IR) injury is increasing. Whether obesity accelerates the severity of IR injury and whether senescence contributes to these conditions remain unclear. We studied the degree of injury and cellular senescence in the IR kidneys and perirenal adipose tissues of high-fat-diet-induced obese mice. C57BL/6 mice fed standard chow or a high-fat diet for 16 weeks were randomized to renal IR or sham group (n = 6-10 each). Renal IR was performed by unilateral clamping of the right renal pedicle for 30 minutes. Six weeks after surgery, renal function, perirenal fat/renal senescence, and histology were evaluated ex vivo. Obese mice showed more renal tubular damage and fibrosis in IR injury than control mice, even though the degree of ischemic insult was comparable. Renal expression of senescence and its secretory phenotype was upregulated in either IR injury or with a high-fat diet and was further increased in the IR kidneys of obese mice. Fat senescence and the expression of tumor necrosis factor alpha were also increased, especially in the perirenal depot of the IR kidneys, with a high-fat diet. A high-fat diet aggravates IR injury in murine kidneys, which is associated, at least in part, with perirenal fat senescence and inflammation. These observations support the exploration of therapeutic targets of the adipo-renal axis in injured obese kidneys.

Phenotypic Differences Exist between BPH/5 Offspring in a Sex‐Dependent Manner

The maternal obesogenic environment is known to play a role in offspring development and metabolism in a sex‐dependent manner. The impact of gestating in obese mothers, with superimposed preeclampsia (PE), on male and female development into adulthood is not completely understood. To investigate this, we utilized the obese BPH/5 female mouse which spontaneously develops hypertension in late gestation, fetal demise, and fetal growth restriction (FGR) while showing excessive gestational weight gain early in pregnancy. We have previously shown that calorie restricted pregnant BPH/5 females have reduction in adiposity and improved outcomes when pair‐feeding is imposed beginning at the time of conception, embryonic day (e) 0.5, including attenuation of inflammatory cytokines at the maternal‐fetal interface and in maternal circulation. We hypothesized that phenotypic differences exist between female and male BPH/5 offspring and that pair‐feeding BPH/5 dams during pregnancy would alter this.To test our hypothesis, we first phenotyped age‐matched juvenile and adult BPH/5 and control C57 mice that gestated in ad libitum fed dams. While adult BPH/5 females are obese compared to C57 female mice, adult BPH/5 males have decreased body weight compared to C57 male mice (n=20, p<0.005). Visceral adipose tissue depots (peri‐renal and peri‐gonadal) in BPH/5 adult females are increased as opposed to BPH/5 males that only show a significant increase in the peri‐renal depot versus controls (3‐fold; n=3, p<0.01). As expected in this genetically hypertensive mouse strain, both female and male BPH/5 adult mice have cardiomegaly compared to controls (6.7±0.3 vs 5.8±0.2 and 8±0.2 vs 5±0.5 heart:body weight ratio, respectively; n=3–13, p<0.05). Interestingly, BPH/5 adult females exhibit hepatomegaly as compared to C57 adult females (25% increase; n=3–9, p<0.05) and BPH/5 adult males do not (n=3, p>0.05).Next, we tested the influence of reducing the maternal obesogenic environment on sex‐dependent pregnancy outcomes in BPH/5. In polygynous litter bearing species, increased numbers of male offspring is advantageous for survival. Therefore, control C57 litters have significantly more male mice (60±5%) than female mice (40±5%) within a litter that survive to weaning age (n=29, p<0.005). BPH/5 show no difference in offspring sex ratios (n=71, p>0.05) and pair‐feeding BPH/5 dams beginning at e0.5 did not change the sex ratios in BPH/5 litters (n=6, p>0.05) nor the body weight in BPH/5 male and female offspring at 2 weeks of age (n=3–17, p>0.05). Pair‐feeding BPH/5 females beginning two weeks before pregnancy and throughout increased live birth weight and litter sizes compared to BPH/5 ad libitum fed pregnancies (n=5; p<0.05). This improvement in fetal demise and FGR was not shown when pair‐feeding began at e0.5 (n=6; p>0.05).Therefore, we believe that pre‐conception reduction in the maternal obesogenic environment may play a greater role in BPH/5 sex‐dependent pregnancy outcomes. Future investigations are necessary to understand the phenotypic differences observed in BPH/5 male versus female mice into adulthood as well as the transgenerational impact of attenuated maternal obesity in pregnancy.

Developmental programming: Adipose depot-specific changes and thermogenic adipocyte distribution in the female sheep

Prenatal testosterone (T)-treated female sheep exhibit an enhanced inflammatory and oxidative stress state in the visceral adipose tissue (VAT) but not in the subcutaneous (SAT), while surprisingly maintaining insulin sensitivity in both depots. In adult sheep, adipose tissue is predominantly composed of white adipocytes which favor lipid storage. Brown/beige adipocytes that make up the brown adipose tissue (BAT) favor lipid utilization due to thermogenic uncoupled protein 1 expression and are interspersed amidst white adipocytes, more so in epicardiac (ECAT) and perirenal (PRAT) depots. The impact of prenatal T-treatment on ECAT and PRAT depots are unknown. As BAT imparts a metabolically healthy phenotype, the depot-specific impact of prenatal T-treatment on inflammation, oxidative stress, differentiation and insulin sensitivity could be dictated by the distribution of brown adipocytes. This hypothesis was tested by assessing markers of oxidative stress, inflammation, adipocyte differentiation, fibrosis and thermogenesis in adipose depots from control and prenatal T (100 mg T propionate twice a week from days 30–90 of gestation) -treated female sheep at 21 months of age. Our results show prenatal T-treatment induces depot-specific changes in inflammation, oxidative stress state, collagen accumulation, and differentiation with changes being more pronounced in the VAT. Prenatal T-treatment also increased thermogenic gene expression in all depots indicative of increased browning with effects being more prominent in VAT and SAT. Considering that inflammatory and oxidative stress are also elevated, the increased brown adipocyte distribution is likely a compensatory response to maintain insulin sensitivity and function of organs in the proximity of respective depots.

Heterogeneity in the perirenal region of humans suggests presence of dormant brown adipose tissue that contains brown fat precursor cells

ObjectiveIncreasing the amounts of functionally competent brown adipose tissue (BAT) in adult humans has the potential to restore dysfunctional metabolism and counteract obesity. In this study, we aimed to characterize the human perirenal fat depot, and we hypothesized that there would be regional, within-depot differences in the adipose signature depending on local sympathetic activity. MethodsWe characterized fat specimens from four different perirenal regions of adult kidney donors, through a combination of qPCR mapping, immunohistochemical staining, RNA-sequencing, and pre-adipocyte isolation. Candidate gene signatures, separated by adipocyte morphology, were recapitulated in a murine model of unilocular brown fat induced by thermoneutrality and high fat diet. ResultsWe identified widespread amounts of dormant brown adipose tissue throughout the perirenal depot, which was contrasted by multilocular BAT, primarily found near the adrenal gland. Dormant BAT was characterized by a unilocular morphology and a distinct gene expression profile, which partly overlapped with that of subcutaneous white adipose tissue (WAT). Brown fat precursor cells, which differentiated into functional brown adipocytes were present in the entire perirenal fat depot, regardless of state. We identified SPARC as a candidate adipokine contributing to a dormant BAT state, and CLSTN3 as a novel marker for multilocular BAT. ConclusionsWe propose that perirenal adipose tissue in adult humans consists mainly of dormant BAT and provide a data set for future research on factors which can reactivate dormant BAT into active BAT, a potential strategy for combatting obesity and metabolic disease.

Dietary energy level affects adipose depot mass but does not impair in vitro subcutaneous adipose tissue response to short-term insulin and tumor necrosis factor-α challenge in nonlactating, nonpregnant Holstein cows

We assessed effects of overfeeding energy to nonlactating and nonpregnant Holstein cows during a length of time similar to a typical dry period on body lipid storage and the abundance of genes related to insulin signaling, inflammation, and ubiquitination in subcutaneous adipose tissue (SAT) in vitro challenged with insulin and recombinant bovine tumor necrosis factor-α. Fourteen cows were randomly assigned to either a high-energy (OVE; net energy for lactation = 1.60 Mcal/kg of dry matter; n = 7) or control (CON; net energy for lactation = 1.30 Mcal/kg of dry matter; n = 7) diet for 6 wk. Immediately after slaughter, liver, kidneys, and mammary gland were separated and weighed. The adipose tissue mass in the omental, mesenteric, and perirenal depots was dissected and weighed. Subcutaneous adipose tissue was collected from the tail-head region and was used as follows: control, bovine insulin (INS) at 1 µmol/L, tumor necrosis factor-α at 5 ng/mL (TNF), and their combination. Despite a lack of difference in final body condition score, OVE cows had greater energy intake and were heavier than CON cows. Furthermore, overfeeding led to greater mass of mesenteric and perirenal adipose, liver, and mammary gland. Overall, SAT incubated with INS had an upregulation of insulin receptor (INSR), interleukin-10 (IL10), small ubiquitin-like modifier 3 (SUMO3), and ubiquitin conjugating enzyme E2I (UBC9), whereas TNF upregulated peroxisome proliferator-activated receptor gamma (PPARG), diacylglycerol O-acyltransferase 2 (DGAT2), interleukin-6 (IL6), nuclear factor kappa B subunit 1 (NFKB1), small ubiquitin-like modifier 2 (SUMO2), and UBC9. Regardless of in vitro treatment, feeding OVE upregulated PPARG, fatty acid synthase (FASN), and insulin induced gene 1 (INSIG1). Abundance of PPARG was greater in SAT of OVE cows cultured individually with INS and TNF. The interaction between diet and in vitro treatment revealed that sterol regulatory element binding transcription factor 1 (SREBF1) had greater abundance in SAT from the CON group in response to culture with INS, whereas SAT from OVE cows had greater SREBF1 abundance in response to culture with TNF. The mRNA abundance of IL6 and NFKB1 was greater in response to TNF treatment and overall in CON cows. Furthermore, SAT from these cows had greater IL10 abundance when cultured with INS and TNF. Overall, data highlighted that overfeeding energy increases adipose tissue mass in part by stimulating transcription of key genes associated with insulin signaling, adipogenesis, and lipogenesis. Because SAT thickness or mass was not measured, the lack of effect of overfeeding on body condition score limits its use to predict overall body lipid storage. An overt inflammatory response in SAT after a 6-wk period of over-consumption of energy could not be discerned.

Transcriptional analysis of adipose tissue during development reveals depot-specific responsiveness to maternal dietary supplementation

Brown adipose tissue (BAT) undergoes pronounced changes after birth coincident with the loss of the BAT-specific uncoupling protein (UCP)1 and rapid fat growth. The extent to which this adaptation may vary between anatomical locations remains unknown, or whether the process is sensitive to maternal dietary supplementation. We, therefore, conducted a data mining based study on the major fat depots (i.e. epicardial, perirenal, sternal (which possess UCP1 at 7 days), subcutaneous and omental) (that do not possess UCP1) of young sheep during the first month of life. Initially we determined what effect adding 3% canola oil to the maternal diet has on mitochondrial protein abundance in those depots which possessed UCP1. This demonstrated that maternal dietary supplementation delayed the loss of mitochondrial proteins, with the amount of cytochrome C actually being increased. Using machine learning algorithms followed by weighted gene co-expression network analysis, we demonstrated that each depot could be segregated into a unique and concise set of modules containing co-expressed genes involved in adipose function. Finally using lipidomic analysis following the maternal dietary intervention, we confirmed the perirenal depot to be most responsive. These insights point at new research avenues for examining interventions to modulate fat development in early life.

Fat Redistribution in an Experimental Model of Hypercortisolism in Rats

Chronic iatrogenic hypercortisolism, which is associated with the inhibition of the adrenal‐pituitary‐ hypothalamic axis, shows characteristic signs that are seen in different forms of Cushing's syndrome. In humans, fat redistribution with increased visceral obesity is one of the main metabolic changes in this syndrome that is related to the development of the metabolic syndrome (insulin resistance, dyslipidemia, and hypertension). However, the mechanisms of fat redistribution between different depots have not been fully elucidated yet, which can be clarified with the establishment of an experimental animal model for Cushing's syndrome.The aim of this study was to characterize the fat redistribution in an experimental model of hypercortisolism in rats (approved by the Ethics Committee in Animal Research [CEUA‐ICB/USP 89/2016]). Male Wistar SPF rats (12 weeks old) were used in experiments. The glucocorticoid (GC) [dexamethasone sodium phosphate 0.5 mg/kg/day] was continuously administered during 4 weeks, by an osmotic pump surgically implanted in the interscapular region. Control (CT) rats were submitted to the same procedure but with NaCl 0.9% administration. Adrenal glands (histologically examined, HE staining) and inguinal subcutaneous, mesenteric and perirenal fat were collected after euthanasia, weighed and the fat was enzymatically digested for adipocyte isolation and morphologic analysis (Motic‐Image Plus 3.0). GC treatment promoted reduction (60%, p<0.0001) of adrenal mass, and the gland atrophy can be verified by qualitative histological analysis. The treatment also promoted intense loss of body mass (150% lower, p<0.0001) and a reduction of 9% (p<0.0001) of the Lee index. However, the rats treated with GC showed an increase of 29% of visceral fat mass represented by mesenteric (p<0.01) and perirenal (p<0.05) depots. Although these depots showed an increased mass, no difference was observed in adipocyte number and volume in the mesenteric fat, whereas in the perirenal, the cell number was higher (p <0.001) and adipocyte volume was lower (p<0.01). Additionally, no difference was observed in inguinal subcutaneous fat mass in GC treated rats. In fact, there was no change in the cellularity of this fat depot, but the adipocyte volume of the GC treated rats was lower in comparison to the CT group. In conclusion, we showed that chronic GC treatment promotes adipose remodeling inducing increased visceral fat mass, reproducing an important characteristic of Cushing's syndrome in humans. This remodeling is certainly associated with several processes that affect lipolysis/lipogenesis, apoptosis/adipogenesis and maybe browning/whitening balances which mechanisms underlying them are now under intense investigation in our laboratory.Support or Funding InformationFAPESP (2016/25129‐4) and CNPq (170545/2017‐2)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Distinct effects of dietary ALA, EPA and DHA on rat adipose oxylipins vary by depot location and sex

Dietary EPA and DHA given together alter oxylipins in adipose tissue. To compare the separate effects of individual dietary n-3 PUFA on oxylipins in different adipose depots (gonadal, mesenteric, perirenal, subcutaneous) in males and females, rats were provided diets containing higher levels of α-linolenic acid (ALA), EPA or DHA. Each n-3 PUFA enhanced its respective oxylipins the most, while effects on other n-3 oxylipins varied. For example: in perirenal and subcutaneous depots, more DHA oxylipins were higher with dietary ALA than with EPA; dietary EPA uniquely decreased 14-hydroxy-docosahexaenoic acid, in contrast to increasing many other DHA oxylipins. The n-3 PUFAs also reduced oxylipins from n-6 PUFAs in order of effectiveness: DHA > EPA > ALA. Diet by sex interactions in all depots except the perirenal depot resulted in higher oxylipins in males given DHA, and higher oxylipins in females given the other diets. Diet and sex effects on oxylipins did not necessarily reflect effects on either their tissue phospholipid or neutral lipid PUFA precursors. These varying diet and sex effects on oxylipins in the different adipose sites indicate that they may have distinct effects on adipose function.

Feed restriction alters lipogenic and adipokine gene expression in visceral and subcutaneous fat depots in lamb

Currently, lipogenic and adipokine gene expression patterns in different fat depots during long-term feed restriction in growing lambs are poorly understood. This study aimed to determine the effects of long-term nutritional deficiency on lipogenic and adipokine gene expression in subcutaneous and visceral fat depots in lambs. Twenty male lambs (4 months old; 21.81±0.75kg body weight) were randomly assigned to either control or feed-restricted groups. After 60 days of maintenance-level feed restriction, femoral, omental, mesenteric, epicardial, and perirenal fat were collected. Gene expressions were estimated by quantitative real-time PCR, and plasma parameters were also determined. The results showed that feed restriction increased the plasma concentration of NEFA (P<0.05) at 30 days, and decreased the plasma concentration of triglycerides, glucose, and insulin (P<0.05) at 30 days and 60 days. Feed restriction decreased lipogenic gene expression (acetyl coenzyme A carboxylase alpha and fatty acid synthase) in all five fat depots. The related key regulating gene PPARγ mRNA decreased (P<0.05) in femoral, omental, and mesenteric fat depots, while sterol regulatory element binding transcription factor 1 decreased (P<0.05) in femoral fat depots. Perilipin, as a barrier to lipolysis, decreased (P<0.05) in femoral, omental and perirenal fat depots of the feed restriction group. Adipose tissue-derived hormone leptin mRNA decreased (P<0.05) in all five fat depots, while adiponectin decreased (P<0.05) only in omental, mesenteric, and epicardial depots. Macrophage marker CD68 mRNA increased (P<0.05) in femoral and mesenteric fat depots. In addition, tumor necrosis factor-α mRNA increased in femoral, omental, and mesenteric depots, whereas IL-1β mRNA increased in femoral and perirenal depots. IL-6 expression decreased in femoral, omental, and epicardial fat depot at the end of feed restriction. Nutritional deficiency induced different changes in lipogenic and adipokine gene expression between visceral and subcutaneous adipose tissue. The decreased leptin, adiponectin, and increased inflammatory factors may inhibit lipogenesis and stimulate lipolysis to protect the body against the threat of starvation.

Mycobacterium tuberculosis can gain access to adipose depots of mice infected via the intra-nasal route and to lungs of mice with an infected subcutaneous fat implant

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis has the remarkable ability to persist as non-replicating forms in the host. These persisters are tolerant to drugs targeting actively replicating bacilli and hence are responsible for the need of an extended duration of anti-tubercular therapy. The anatomical locations and cell types housing Mtb persisters are being investigated in the recent times. Adipose tissue and the adipocytes are proposed niches of Mtb persisters. In the present study, we carried out experiments in the immunocompetent Swiss mice to see the dissemination of Mtb from lungs to adipose tissue and vice versa. Mice infected intra-nasally with ∼106, 104 or 102 bacilli harboured Mtb in various adipose depots distal to the lungs such as the visceral, subcutaneous and peri-renal depots. The dissemination was minimal at two weeks post-infection, as evident from culture negative adipose tissue samples. But at seven weeks post-infection, viable Mtb could be detected in 78%, 66% and 66% of the samples from high, moderate and low dose-infection groups respectively. In a separate experiment, Mtb-infected pre-adipocytes were implanted subcutaneously to un-infected mice. At five weeks post-implantation, the intact implants had a mean 7 ± 0.53 log10 CFUs/100 mg tissue, while the lungs had a mean 3.25 ± 0.32 log10 CFUs/100 mg tissue. In conclusion, the study shows that Mtb can disseminate from lungs to distant adipose depots and vice versa.

Carcass traits, meat yield and fatty acid composition of adipose tissues and Supraspinatus muscle in goats fed blend of canola oil and palm oil.

BackgroundDietary fats can alter the deposition and distribution of body fats in ruminants. The deposition and distribution of body fat play a vital role in the quality of ruminant carcasses and are of great commercial value since they influence the profitability and consumer acceptability of ruminant meat. The current study examined the effects of dietary blend of 80 % canola oil and 20 % palm oil (BCPO) on carcass characteristics, meat yield and accretion of fatty acid (FA) in subcutaneous, omental, perirenal, and mesentery adipose depots and m. supraspinatus (SS) in goats.MethodsTwenty four Boer crossbred bucks (BW 20.54 ± 0.47 kg) were randomly assigned to diets containing on DM basis 0, 4 and 8 % BCPO, fed for 100 d and harvested.ResultsDiet had no effect (P > 0.05) on slaughter weight, dressing percentage, carcass and non-carcass components, meat yield, color, moisture and carotenoid contents and weight of adipose tissues in goats. The proportion of C18:1n-9 and cis-9 trans-11 CLA in the omental, perirenal and SS was higher (P < 0.05) in goats fed 4 and 8 % BCPO compared with the control goats. Dietary BCPO reduced (P < 0.05) the proportion of C14:0 in the omental, perirenal and mesentery depots, C18:0 in the perirenal depot, C16:0 in the SS and C16:1n-7 in the SS, omental and perirenal tissues. Dietary BCPO enhanced the proportion of C18:1 trans-11 Vaccenic and C18:3n-3 in SS and C20:5n-3 in SS and mesentery depot. No significant changes were found in the FA composition of subcutaneous depot.ConclusionsResults indicate that dietary BCPO can be utilized to alter the FA composition of adipose tissues without detrimental effects on carcass characteristics in goats. Nonetheless, dietary BCPO is not an effective repartitioning agent for body fats in goats.

Activation of classical brown adipocytes in the adult human perirenal depot is highly correlated with PRDM16-EHMT1 complex expression.

Brown fat generates heat to protect against cold and obesity. Adrenergic stimulation activates the thermogenic program of brown adipocytes. Although the bioactivity of brown adipose tissue in adult humans had been assumed to very low, several studies using positron emission tomography–computed tomography (PET–CT) have detected bioactive brown adipose tissue in adult humans under cold exposure. In this study, we collected adipose tissues obtained from the perirenal regions of adult patients with pheochromocytoma (PHEO) or non-functioning adrenal tumors (NF). We demonstrated that perirenal brown adipocytes were activated in adult patients with PHEO. These cells had the molecular characteristics of classical brown fat rather than those of beige/brite fat. Expression of brown adipose tissue markers such as uncoupling protein 1 (UCP1) and cell death-inducing DFFA-like effector A (CIDEA) was highly correlated with the amounts of PRD1-BF-1-RIZ1 homologous domain-containing protein-16 (PRDM16) – euchromatic histone-lysine N-methyltransferase 1 (EHMT1) complex, the key transcriptional switch for brown fat development. These results provide novel insights into the reconstruction of human brown adipocytes and their therapeutic application against obesity and its complications such as type 2 diabetes.

Characterization of brown adipose tissue in the human perirenal depot.

To characterize brown adipose tissue (BAT) in the human perirenal adipose tissue depot. Perirenal adipose tissue biopsies were obtained from 55 healthy kidney donors. Expression analysis was performed using microarray, real-time PCR, immunoblotting and immunohistochemistry. Additional studies using human stem cells were performed. UCP1 gene expression analysis revealed a large intra-individual variation in the perirenal adipose tissue biopsies. Both multi- and unilocular UCP1-positive adipocytes were detected in several of the adipose tissue samples analyzed by immunohistochemical staining. Microarray analysis identified 54 genes that were overexpressed in UCP1-positive perirenal adipose tissue. Real-time PCR analysis of BAT candidate genes revealed a set of genes that were highly correlated to UCP1 and a set of three transcription factor genes (PRDM16, PGC1α, and RXRγ) that were highly correlated to each other. RXRγ displayed nuclear immunoreactivity in brown adipocytes and an increased gene expression during brown adipogenesis in human stem cells. Our data provides the first molecular characterization of BAT in the perirenal adipose tissue depot. Furthermore, it highlights the transcription factor RXRγ as a new player in BAT development.

Preferential impact of pregnancy-associated plasma protein-A deficiency on visceral fat in mice on high-fat diet

Accumulation of visceral fat, more so than subcutaneous fat, is strongly associated with severe metabolic complications. However, the factors regulating depot-specific adipogenesis are poorly understood. In this study, we show differential expression of pregnancy-associated plasma protein-A (PAPP-A), a secreted regulator of local insulin-like growth factor (IGF) action, in adipose tissue of mice. PAPP-A mRNA expression was fivefold higher in visceral (mesenteric) fat compared with subcutaneous (inguinal, subscapular), perirenal, and brown fat of mice. To investigate the possible role of depot-specific PAPP-A expression in fat accumulation, wild-type (WT) and PAPP-A knockout (KO) mice were fed a high-fat diet (HFD) for up to 20 wk. Adipocyte size increased in subcutaneous and perirenal depots similarly in WT and PAPP-A KO mice. However, fat cell size and in vivo lipid uptake were significantly reduced in mesenteric fat of PAPP-A KO compared with WT mice. After 20 wk on HFD, phosphorylation of AKT, a downstream signaling intermediate of IGF-I and insulin receptor activation, was significantly decreased by 50% in mesenteric compared with subcutaneous fat in WT mice, but was significantly increased threefold in mesenteric compared with subcutaneous fat in PAPP-A KO mice. This appeared to be because of enhanced insulin-stimulated signaling in mesenteric fat of PAPP-A KO mice. These data establish fat depot-specific expression of PAPP-A and indicate preferential impact of PAPP-A deficiency on visceral fat in the mouse that is associated with enhanced insulin receptor signaling. Thus, PAPP-A may be a potential target for treatment and/or prevention strategies for visceral obesity and related morbidities.

Clavicular brown adipose tissue has a different origin from the perirenal depot that is indicative of muscle related lineage

Multiple evidence from human studies indicates that the primary sites for brown adipose tissue in humans are the bilateral clavicular depots. In this study we aimed to identify an analogous region in the young sheep and whether it contained microRNA (MIR) specific to muscle or adipose tissue. This was compared with perirenal‐abdominal adipose tissue which represents the major fat depot in young sheep.Four triplet‐bearing mothers were entered into the study and a randomly selected triplet euthanased at 1, 7 or 28 days of age for adipose tissue sampling. Gene expression for target genes was determined by quantitative reverse transcriptase polymerase chain reaction.MIR 206 was highly abundant in skeletal muscle and was also detectable in BAT sampled from the clavicular but not perirenal depot at all sampling ages. This was despite an age related decline in UCP1 and related genes, whereas gene expression of RIP140 increased with age.Our study suggests a different cell lineage in clavicular adipose tissue compared with other BAT depots in the young sheep. Despite showing beige characteristics with increasing age, retention of some muscular origins may mean it is more response to environmental challenges aimed at promoting BAT function. The young sheep, therefore, provides a novel model for examining the developmental process of adipose transformation in early life.

Molecular and histological evidence of brown adipose tissue in adult cats

Brown adipose tissue (BAT) can influence glucose, lipid, and energy metabolism in rodents. Active BAT is now known to be present in adult humans, and interventions targeting BAT are being investigated for the treatment of human obesity and disorders of glucose and lipid metabolism. Domestic cats, like humans, are at increasing risk for obesity and diabetes but little is known about the presence and role of BAT in adult cats. The purpose of this study was to determine if brown adipocytes, identifiable by histological features and molecular markers, were present in the fat depots of adult cats. Adipose tissue samples from intrascapular, perirenal, and subcutaneous depots of eleven 8-12 year old cats (6 lean, 5 obese), were analyzed by real-time PCR for brown adipocyte markers uncoupling protein 1 (UCP1) and Type II iodothyronine 5'deiodinase (D2), by histological examination and by immunohistochemistry for UCP1. UCP1 mRNA was detectable in interscapular and subcutaneous depots in all cats, and in the perirenal depot in 10/11 cats. D2 mRNA was detectable in all depots from all cats. Multilocular adipocytes were identified in the interscapular depots of 4/11 cats and these were positive for UCP1 immunoreactivity. The results demonstrate that UCP1-expressing brown adipocytes are present in multiple depots of adult lean and long-term obese cats, even at 8-12 years of age. It is possible that dietary components or pharmacological agents that influence brown fat activity could exert a relevant biological effect in cats.

Maternal obesity upregulates fatty acid and glucose transporters and increases expression of enzymes mediating fatty acid biosynthesis in fetal adipose tissue depots1

Maternal nutrient restriction leads to alteration in fetal adipose tissue, and offspring from obese mothers have an increased risk of developing obesity. We hypothesized that maternal obesity increases fetal adipogenesis. Multiparous ewes (Columbia/Rambouillet cross 3 to 5 yr of age) carrying twins were assigned to a diet of 100% (Control; CON; n = 4) or 150% (Obese; OB, n = 7) of NRC maintenance requirements from 60 d before conception until necropsy on d 135 of gestation. Maternal and fetal plasma were collected and stored at -80°C for glucose and hormone analyses. Fetal measurements were made at necropsy, and perirenal, pericardial, and subcutaneous adipose tissues were collected from 7 male twin fetuses per group and snap frozen at -80°C. Protein and mRNA expression of fatty acid translocase [cluster of differentiation (CD) 36], fatty acid transport proteins (FATP) 1 and 4, insulin-sensitive glucose transporter (GLUT-4), fatty acid synthase (FASN), and acetyl-coA carboxylase (ACC) was evaluated. Fetal weight was similar, but fetal carcass weight (FCW) was reduced (P < 0.05) in OB versus CON fetuses. Pericardial and perirenal adipose tissue weights were increased (P < 0.05) as a percentage of FCW in OB versus CON fetuses, as was subcutaneous fat thickness (P < 0.001). Average adipocyte diameter was greater (P < 0.01) in the perirenal fat and the pericardial fat (P = 0.06) in OB fetuses compared with CON fetuses. Maternal plasma showed no difference (P > 0.05) in glucose or other hormones, fetal plasma glucose was similar (P = 0.42), and cortisol, IGF-1, and thyroxine were reduced (P ≤ 0.05) in OB fetuses compared with CON fetuses. Protein and mRNA expression of CD 36, FATP 1 and 4, and GLUT-4 were increased (P ≤ 0.05) in all fetal adipose depots in OB versus CON fetuses. The mRNA expression of FASN and ACC was increased (P < 0.05) in OB vs. CON fetuses in all 3 fetal adipose tissue depots. Fatty acid concentrations were increased (P = 0.01) in the perirenal depot of OB versus CON fetuses, and specific fatty acid concentrations were altered (P < 0.05) in subcutaneous and pericardial adipose tissue because of maternal obesity. In conclusion, maternal obesity was associated with increased fetal adiposity, increased fatty acid and glucose transporters, and increased expression of enzymes mediating fatty acid biosynthesis in adipose depots. These alterations, if maintained into the postnatal period, could predispose the offspring to later obesity and metabolic disease.

Body composition changes and inhibition of fat development in vivo implicates androgen in regulation of stem cell lineage allocation

Androgens regulate body composition in youth and declining testosterone that occurs with aging is associated with muscle wasting, increased fat mass and osteopenia. Transgenic mice with targeted androgen receptor (AR) over-expression in mesenchymal stem cells (MSC) were generated to explore the role of androgen signaling in the regulation of body composition. Transgenic males, but not females, were shorter and have reduced body weight and visceral fat accumulation. Dual-energy X-ray absorptiometry (DXA) revealed significant reductions in fat mass with a reciprocal increase in lean mass, yet no difference in food consumption or locomotor activity was observed. Adipose tissue weight was normal in brown fat but reduced in both gonadal and perirenal depots, and reduced hyperplasia was observed with smaller adipocyte size in visceral and subcutaneous white adipose tissue. Although serum leptin, adiponectin, triglyceride, and insulin levels were no different between the genotypes, intraperitoneal glucose tolerance testing (IPGTT) showed improved glucose clearance in transgenic males. High levels of the AR transgene are detected in MSCs but not in mature fat tissue. Reduced fibroblast colony forming units indicate fewer progenitor cells resident in the marrow in vivo. Precocious expression of glucose transporter 4 (GLUT4), peroxisome proliferator-activated receptor γ (PPARγ), and CCAAT enhancer-binding protein α (C/EBPα) was observed in proliferating precursor cultures from transgenic mice compared to controls. In more mature cultures, there was little difference between the genotypes. We propose a mechanism where enhanced androgen sensitivity can alter lineage commitment in vivo to reduce progenitor number and fat development, while increasing the expression of key factors to promote smaller adipocytes with improved glucose clearance.

Distribution and Development of Brown Adipocytes in the Murine and Human Adipose Organ

Murine white and brown adipocytes are found together in dissectible visceral and subcutaneous fat depots supplied by specific vessels and nerves, forming a multi-depot organ with plastic properties. Many of the anatomo-physiological features of murine fat depots apply to humans.

Type-1 Diabetes Induces Depot-Specific Alterations in Adipocyte Diameter and Mass of Adipose Tissues in the Rat

Type-1 diabetes (T1D) is a metabolic disorder associated with massive reduction in mass of adipose tissue. Measuring cell diameter, an index of fat metabolism, we determined depot-specific alterations in weight of adipose tissue, fat cell diameter and size heterogeneity and distribution at 5 depots in streptozotocin (STZ)-induced diabetic rats. T1D was induced by a single injection of STZ. Seven days after the injection, fat depots were isolated, weighted, washed and maintained in tissue culture medium. Using a microscope equipped with calibrated micrometer, cell diameter as well as size distribution pattern and heterogeneity of adipocytes were determined in fresh tissue slices of subcutaneous (SC), proximal epididymal (PE), distal epididymal (DE), perirenal (PR) and retroperitoneal (RP) fat depots. The T1D induced marked reductions in fat mass and mean of fat cell diameter at all depots. The most affected depot was the SC. With the exception of PE, adipocytes at all depots showed significant increases in size heterogeneity. The effect of the diabetes on mean fat cell diameter and size heterogeneity was minimal at PE depot. Depots with similar cell size distribution pattern exhibited similar fat mass reduction. However, the DE depot with a unique cell size distribution pattern showed a fat mass reduction similar to that of PE and PR depots. These data indicate that T1D induces a massive fat mass reduction in a reasonably depot-specific manner and that the fat depots close to survival organs are less vulnerable to fat mobilization. Moreover, peculiar disagreement between cell size distribution and heterogeneity as well as the level of fat mass reduction at DE and PE depots suggests that not only cell size and heterogeneity but also local factors may play roles in depot-specific fat mobilization.