Distinct Adipose Tissue Depots Research Articles

β-Adrenergic blockade attenuates adverse adipose tissue responses after burn.

Severe burn injuries are defined by a prolonged hypermetabolic response characterized by increases in resting energy expenditure, systemic catabolism, and multi-organ dysfunction. The sustained elevation of catecholamines following a burn injury is thought to significantly contribute to this hypermetabolic response, leading to changes in adipose tissue such as increased lipolysis and the browning of subcutaneous white adipose tissue (WAT). Failure to mitigate these adverse changes within the adipose tissue has been shown to exacerbate the post-burn hypermetabolic response and lead to negative outcomes. Propranolol, a non-selective β-blocker, has been clinically administered to improve outcomes of pediatric and adult burn patients, but there is inadequate knowledge of its effects on the distinct adipose tissue depots. In this study, we investigated the adipose depot-specific alterations that occur in response to burn injury. Moreover, we explored the therapeutic effects of β-adrenoceptor blockade via the drug propranolol in attenuating these burn-induced pathophysiological changes within the different fat depots. Using a murine model of thermal injury, we show that burn injury induces endoplasmic reticulum (ER) stress in the epididymal (eWAT) but not in the inguinal (iWAT) WAT depot. Conversely, burn injury induces the activation of key lipolytic pathways in both eWAT and iWAT depots. Treatment of burn mice with propranolol effectively mitigated adverse burn-induced alterations in the adipose by alleviating ER stress in the eWAT and reducing lipolysis in both depots. Furthermore, propranolol treatment in post-burn mice attenuated UCP1-mediated subcutaneous WAT browning following injury. Overall, our findings suggest that propranolol serves as an effective therapeutic intervention to mitigate the adverse changes induced by burn injury, including ER stress, lipotoxicity, and WAT browning, in both adipose tissue depots. KEY MESSAGES: Burn injury adversely affects adipose tissue metabolism via distinct changes in both visceral and subcutaneous adipose depots. Propranolol, a non-selective β-adrenergic blocker, attenuates many of the adverse adipose tissue changes mediated by burn injury.

TLCD4 as Potential Transcriptomic Biomarker of Cold Exposure.

(1) Background: Cold exposure induces metabolic adaptations that can promote health benefits, including increased energy disposal due to lipid mobilization in adipose tissue (AT). This study aims to identify easily measurable biomarkers mirroring the effect of cold exposure on AT. (2) Methods: Transcriptomic analysis was performed in peripheral blood mononuclear cells (PBMCs) and distinct AT depots of two animal models (ferrets and rats) exposed to cold, and in PBMCs of cold-exposed humans. (3) Results: One week of cold exposure (at 4 °C) affected different metabolic pathways and gene expression in the AT of ferrets, an animal model with an AT more similar to humans than that of rodents. However, only one gene, Tlcd4, was affected in the same way (overexpressed) in aortic perivascular and inguinal AT depots and in PBMCs, making it a potential biomarker of interest. Subsequent targeted analysis in rats showed that 1 week at 4 °C also induced Tlcd4 expression in brown AT and PBMCs, while 1 h at 4 °C resulted in reduced Tlcd4 mRNA levels in retroperitoneal white AT. In humans, no clear effects were observed. Nevertheless, decreased PBMC TLCD4 expression was observed after acute cold exposure in women with normal weight, although this effect could be attributed to short-term fasting during the procedure. No effect was evident in women with overweight or in normal-weight men. (4) Conclusions: Our results obtained for different species point toward TLCD4 gene expression as a potential biomarker of cold exposure/fat mobilization that could tentatively be used to address the effectiveness of cold exposure-mimicking therapies.

Depot-specific adaption of adipose tissue for different exercise approaches in high-fat diet/streptozocin-induced diabetic mice.

Background: Adipose tissue pathology plays a crucial role in the pathogenesis of type 2 diabetes mellitus. Understanding the impact of exercise training on adipose tissue adaptation is of paramount importance in enhancing metabolic health. In this study, we aimed to investigate the effects of various exercise modalities on three distinct adipose tissue depots, namely, interscapular brown adipose tissue (iBAT), subcutaneous white adipose tissue (sWAT), and epididymal white adipose tissue (eWAT), in a murine model of diabetes. Methods: Male C57BL/6J mice received a 12-week high-fat diet and a single injection of streptozotocin, followed by an 8-week exercise intervention. The exercise intervention included swimming, resistance training, aerobic exercise, and high-intensity interval training (HIIT). Results: We found that exercise training reduced body weight and body fat percentage, diminished adipocyte size and increased the expression of mitochondria-related genes (PGC1, COX4, and COX8B) in three adipose tissue depots. The effects of exercise on inflammatory status include a reduction in crown-like structures and the expression of inflammatory factors, mainly in eWAT. Besides, exercise only induces the browning of sWAT, which may be related to the expression of the sympathetic marker tyrosine hydroxylase. Among the four forms of exercise, HIIT was the most effective in reducing body fat percentage, increasing muscle mass and reducing eWAT adipocyte size. The expression of oxidative phosphorylation and thermogenesis-related genes in sWAT and eWAT was highest in the HIIT group. Conclusion: When targeting adipose tissue to improve diabetes, HIIT may offer superior benefits and thus represents a more advantageous choice.

Impact of Dysfunctional Adipose Tissue Depots on the Cardiovascular System.

Obesity with its associated complications represents a social, economic and health problem of utmost importance worldwide. Specifically, obese patients carry a significantly higher risk of developing cardiovascular disease compared to nonobese individuals. Multiple molecular mechanisms contribute to the impaired biological activity of the distinct adipose tissue depots in obesity, including secretion of proinflammatory mediators and reactive oxygen species, ultimately leading to an unfavorable impact on the cardiovascular system. This review summarizes data relating to the contribution of the main adipose tissue depots, including both remote (i.e., intra-abdominal, hepatic, skeletal, pancreatic, renal, and mesenteric adipose fat), and cardiac (i.e., the epicardial fat) adipose locations, on the cardiovascular system. Finally, we discuss both pharmacological and non-pharmacological strategies aimed at reducing cardiovascular risk through acting on adipose tissues, with particular attention to the epicardial fat.

1230-P: Isolation of Functional Endothelial Progenitor Cells from Human Adipose Tissue

Endothelial progenitor cells (EPCs) are key for angiogenic responses in multiple tissues and mediate a coordinate augmentation of the capillary network as adipose tissue (AT) expands in response to positive energy balance. However, isolation and culture of EPCs from human AT has been difficult. Here we describe a new method for obtaining well-characterized EPCs from human AT. Subcutaneous and visceral AT specimens (approximately 1-2 g) were obtained from 10-20 obese subjects by needle biopsy of abdominal subcutaneous AT and removal of omental AT fragments during abdominal surgery, respectively. Human EPCs were isolated from both the digested (SVCI) and undigested (SVCII) stromal vascular fractions of AT by anti-CD31 beads. After 5 days of in vitro culture, EPCs from SVCII exhibited an endothelial-like cobblestone morphology as compared to EPCs from SVCI. Flow cytometry analysis showed that the percentage of CD31+ and CD144+ cells was much higher in the SVCII compared to SVCI fraction (SVCII: CD31 97.9±2.9%, CD144 93.3±4.7%; SVCI: CD31 4.0±1.2%, CD144 3.8±0.7%). Immunofluorescence staining demonstrated that CD31+ EPCs from SVCII expressed Von Willebrand Factor (vWF) and VE-cadherin. Additionally, significantly higher mRNA and protein levels of CD31, E-selectin, e-NOS, VEGFR, and CD34 were found in CD31+ EPCs from SVCII than in control cells (CD31- cells from SVCI). EPCs from SVCII maintained the expression of endothelial markers (CD144 mRNA and protein levels) up to the fourth cell passage. Lastly, CD31+ EPCs from SVCII, but not control cells, were able to form tubes in 3D scaffolds (Matrigel) resembling capillary structures, as well as to incorporate acetylated LDL in vitro. Thus, we have successfully isolated EPCs with high proliferative potential and specific functional properties from the human AT. This will potentially increase our understanding of AT biology particularly in relation to altered expansion of distinct AT depots in human obesity. Disclosure C. Caccioppoli: None. S. Perrini: None. V. Genchi: None. R. Doria: None. G. Palma: None. A. Cignarelli: None. A. Natalicchio: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Sanofi. L. Laviola: Advisory Panel; Self; A. Menarini Diagnostics, Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis, Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Medtronic. F. Giorgino: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Research Support; Self; Lilly Diabetes, Roche Diabetes Care.

Tissue-specific fatty acid composition, cellularity, and gene expression in diverse cattle breeds

The nutritional quality of beef relates to the fatty acid (FA) composition of bovine adipose tissue. Those molecular mechanisms that induce the differing amounts and composition of fat in cattle breeds according to age at maturity and purpose of production remain unclear. Therefore, this study investigated the composition of total FAs, adipocyte size, and expression of some key genes involved in several adipogenesis and lipogenesis pathways measured in distinct adipose tissue depots from bulls of the genetically diverse cattle breeds Aberdeen Angus (n = 9), Gascon (n = 10), Holstein (n = 9), and Fleckvieh (n = 10). The animals were finished under identical housing and feeding conditions until slaughter at a similar age of 17 months. After slaughter, cod adipose tissue (CAT), subcutaneous adipose tissue (SAT), and M. longissimus lumborum (MLL) samples were collected. The saturated FA proportions were higher (P < .01) in CAT than in SAT across all breeds, whereas monounsaturated FA proportions were consistently higher (P < .001) in SAT compared to CAT and MLL. Aberdeen Angus bulls were distinguished from the other breeds in the proportions of mostly de novo synthesized C14:0, C16:0, C14:1n-5, C16:1n-7, and conjugated linoleic acid (P < .05). Adipocyte size decreased in the order CAT > SAT > MLL, and the largest adipocytes were observed in CAT of Holstein bulls (P < .05). Gene expression differences were more pronounced between adipose tissue depots than between breeds. The expression levels of ACACA, FASN, and SCD1 genes were related to tissue-specific, and to a lesser extent also breed-specific, differences in FA composition.

Adipose tissue area as a predictor for the efficacy of apatinib in platinum-resistant ovarian cancer: an exploratory imaging biomarker analysis of the AEROC trial

BackgroundVascular endothelial growth factor (VEGF)-targeted therapy is effective in patients with ovarian cancer. Whether adipose tissue (AT) could predict the efficacy of VEGF receptor (VEGFR) inhibitors in ovarian cancer is unknown. We aimed to evaluate the ability of distinct AT depots to predict the efficacy of apatinib, a VEGFR inhibitor, in recurrent ovarian cancers included in the AEROC trial.MethodsThe AEROC was a single-arm phase 2 trial of apatinib and oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer. Apatinib was administered continuously, and oral etoposide was administered every 21 days for a maximum of six cycles. This was a post hoc study based on the AEROC trial. Areas of visceral AT (VAT), subcutaneous AT (SAT), and intermuscular AT (IMAT) were measured using computed tomography scan at baseline to assess their association with the objective response rate, progression-free survival, and overall survival.ResultsOf the 35 treated patients, 31 patients with at least one post-baseline efficacy assessment by computed tomography scan were included in this study. After adjusting for apatinib exposure, high VAT (odds ratio [OR], 0.16; 95% confidence interval [CI], 0.03–0.90, P = 0.037) and SAT (OR, 0.16; 95% CI, 0.03–0.87, P = 0.034) were significantly associated with a higher objective response rate. Further, decreased risks of disease progression and death were associated with high VAT (hazard ratio [HR], 0.39; 95% CI, 0.17–0.92, P = 0.031, and HR, 0.12; 95% CI, 0.04–0.40, P < 0.001, respectively), SAT (HR, 0.35; 95% CI, 0.15–0.83, P = 0.027, and HR, 0.24; 95% CI, 0.08–0.67, P = 0.007, respectively), and IMAT (HR, 0.20; 95% CI, 0.06–0.74, P = 0.016, and HR, 0.13; 95% CI, 0.03–0.62, P = 0.011, respectively).ConclusionsHigh areas of VAT, SAT, and IMAT were significantly associated with better outcomes in patients with platinum-resistant or platinum-refractory ovarian cancer who received VEGFR inhibitors. AT assessments may be valuable as patient-specific imaging biomarkers for predicting response to VEGFR inhibitors.Trial registrationClinicalTrials.gov identifier: NCT02867956.

Inflammation and adiposity: new frontiers in atrial fibrillation.

The aetiology of atrial fibrillation (AF) remains poorly understood, despite its growing prevalence and associated morbidity, mortality, and healthcare costs. Obesity is implicated in myriad different disease processes and is now recognized a major risk factor in the pathogenesis of AF. Moreover, the role of distinct adipose tissue depots is a matter of intense scientific interest with the depot directly surrounding the heart-epicardial adipose tissue (EAT) appearing to have the greatest correlation with AF presence and severity. Similarly, inflammation is implicated in the pathophysiology of AF with EAT thought to act as a local depot of inflammatory mediators. These can easily diffuse into atrial tissue with the potential to alter its structural and electrical properties. Various meta-analyses have indicated that EAT size is an independent risk factor for AF with adipose tissue expansion being inevitably associated with a local inflammatory process. Here, we first briefly review adipose tissue anatomy and physiology then move on to the epidemiological data correlating EAT, inflammation, and AF. We focus particularly on discussing the mechanistic basis of how EAT inflammation may precipitate and maintain AF. Finally, we review how EAT can be utilized to help in the clinical management of AF patients and discuss future avenues for research.

Insulin selectively reduces mitochondrial uncoupling in brown adipose tissue in mice.

The purpose of the present study was to determine the effects of prolonged hyperinsulinemia on mitochondrial respiration and uncoupling in distinct adipose tissue depots. Sixteen-week-old male mice were injected daily with placebo or insulin to induce an artificial hyperinsulinemia for 28 days. Following the treatment period, mitochondrial respiration and degree of uncoupling were determined in permeabilized perirenal, inguinal, and interscapular adipose tissue. White adipose tissue (WAT) mitochondria (inguinal and perirenal) respire at substantially lower rates compared with brown adipose tissue (BAT). Insulin treatment resulted in a significant reduction in mitochondrial respiration in inguinal WAT (iWAT) and interscapular BAT (iBAT), but not in perirenal WAT (pWAT). Furthermore, these changes were accompanied by an insulin-induced reduction in UCP-1 (uncoupling protein 1) and PGC-1α in iWAT and iBAT only, but not in pWAT or skeletal muscle. Compared with adipose tissue mitochondria in placebo conditions, adipose tissue from hyperinsulinemic mice manifested a site-specific reduction in mitochondrial respiration probably as a result of reduced uncoupling. These results may help explain weight gain so commonly seen with insulin treatment in type 2 diabetes mellitus.

Weight loss independent changes in adipose tissue macrophage and T cell populations after sleeve gastrectomy in mice

ObjectiveIn addition to adipocytes, adipose tissue contains large numbers of immune cells. A wide range of evidence links the activity of these cells to regulation of adipocyte and systemic metabolic function. Bariatric surgery improves several aspects of metabolic derangements and at least some of these effects occur in a weight-loss independent manner. We sought to investigate the impact of vertical sleeve gastrectomy (VSG) on adipose immune cell frequencies. MethodsWe analyzed the frequencies of immune cells within distinct adipose tissue depots in obese mice that had VSG or sham surgery with a portion of the latter group pair-fed such that their body mass was matched to the VSG animals. ResultsWe demonstrate that VSG induced a shift in the epididymal adipose tissue leukocyte profile including increased frequencies of CD11c− macrophages, increased frequencies of T cells (CD4+, CD8+, and CD4−/CD8− T cells all increased), but a significantly decreased frequency of adipose tissue dendritic cells (ATDC) that, despite the continued high fat feeding of the VSG group, dropped below control diet levels. ConclusionsThese results indicate that VSG induces substantial changes in the immune populations residing in the adipose depots independent of weight loss.

Adipose tissue development and the molecular regulation of lipid metabolism.

The production of new adipocytes is required to maintain adipose tissue mass and involves the proliferation and differentiation of adipocyte precursor cells (APCs). In this review, we outline new developments in understanding the phenotype of APCs and provide evidence suggesting that APCs differ between distinct adipose tissue depots and are affected by obesity. Post-mitotic mature adipocytes regulate systemic lipid homeostasis by storing and releasing free fatty acids, and also modulate energy balance via the secretion of adipokines. The review highlights recent advances in understanding the cellular and molecular mechanisms regulating adipocyte metabolism, with a particular focus on lipolysis regulation and the involvement of microribonucleic acids (miRNAs).

Enrichment of IFN-γ producing cells in different murine adipose tissue depots upon infection with an apicomplexan parasite.

Here we report that lean mice infected with the intracellular parasite Neospora caninum show a fast but sustained increase in the frequency of IFN-γ-producing cells noticeable in distinct adipose tissue depots. Moreover, IFN-γ-mediated immune memory could be evoked in vitro in parasite antigen-stimulated adipose tissue stromal vascular fraction cells collected from mice infected one year before. Innate or innate-like cells such as NK, NK T and TCRγδ+ cells, but also CD4+ and CD8+ TCRβ+ lymphocytes contributed to the IFN-γ production observed since day one of infection. This early cytokine production was largely abrogated in IL-12/IL23 p40-deficient mice. Moreover, production of IFN-γ by stromal vascular fraction cells isolated from these mice was markedly lower than that of wild-type counterparts upon stimulation with parasite antigen. In wild-type mice the increased IFN-γ production was concomitant with up-regulated expression of genes encoding interferon-inducible GTPases and nitric oxide synthase, which are important effector molecules in controlling intracellular parasite growth. This increased gene expression was markedly impaired in the p40-deficient mice. Overall, these results show that NK cells but also diverse T cell populations mediate a prompt and widespread production of IFN-γ in the adipose tissue of N. caninum infected mice.

White, brite, and brown adipocytes: the evolution and function of a heater organ in mammals

Brown fat is a specialized heater organ in eutherian mammals. In contrast to the energy storage function of white adipocytes, brown adipocytes dissipate nutrient energy by uncoupling of mitochondrial oxidative phosphorylation, which depends on uncoupling protein 1 (UCP1). UCP1, as well as UCP2 and UCP3, belong to the family of mitochondrial carriers inserted into the inner mitochondrial membrane for metabolite trafficking between the matrix and the intermembrane space. UCP1 transports protons into the mitochondrial matrix when activated by a rise in free fatty acid levels in the cell. This UCP1-dependant proton leak drives high oxygen consumption rates in the absence of ATP synthesis and dissipates proton motive force as heat. The enormous heating capacity of brown fat is supported by dense vascularization, high rates of tissue perfusion, and high mitochondrial density in brown adipocytes.It has been known for more than 50 years that nonshivering thermogenesis in brown fat serves to maintain body temperature of neonates and small mammals in cold environments, and is used by hibernators for arousal from torpor. It has been speculated that the development of brown fat as a new source for nonshivering thermogenesis provided mammals with a unique advantage for survival in the cold. Indeed brown fat and UCP1 is found in ancient groups of mammals, like the afrotherians and marsupials. In the latter, however, the thermogenic function of UCP1 and brown fat has not been demonstrated as of yet. Notably, orthologs of all three mammalian UCP genes are also present in the genomes of bony fishes and in amphibians. Molecular phylogeny reveals a striking increase in the substitution rate of UCP1 between marsupial and eutherian lineages. At present, it seems that UCP1 only gained thermogenic function in brown adipocytes of eutherian mammals, whereas the function of UCP1 and that of the other UCPs in ectotherms remains to be identified.Evolution of thermogenic function required expression of UCP1 in a brown-adipocyte-like cell equipped with high mitochondrial density embedded in a well-vascularized tissue. Brown-adipocyte-like cells in white adipose tissue, called “brite” (brown-in-white) or “beige” adipocytes, emerge during adipogenesis and in response to cold exposure in anatomically distinct adipose tissue depots of juvenile and adult rodents. These brite adipocytes may resemble the archetypical brown adipocyte in vertebrate evolution. It is therefore of interest to elucidate the molecular mechanisms of brite adipocyte differentiation, study the bioenergetic properties of these cells, and search for the presence of related brown-adipocyte-like cells in nonmammalian vertebrates.

Influence of Depot Origin on the Susceptibility of Adipose Progenitor Cells to Cell Death

Nutrient excess and a sedentary lifestyle lead to an accumulation of adipose tissue (obesity) through an increase in adipocyte size (hypertrophy) and number (hyperplasia). Hypertrophic obesity results in dysfunctional adipocytes associated with adipose tissue inflammation and insulin resistance. On the other hand, hyperplastic adipose tissue expansion is linked to preservation of insulin sensitivity. Metabolically functional adipose tissue expansion via hyperplasia may require an adequate number of responsive adipose progenitor cells. Distinct adipose tissue depots vary with respect to functional responses, such as lipolysis and adipogenesis. The aim of this study was to investigate the influence of depot origin on the susceptibility of adipose progenitor cells to cell death. Using serum deprivation alone or in the presence of 25nM tumor necrosis factor (TNF) α, visceral omental (OM) versus abdominal subcutaneous (SC) adipose progenitor cells displayed a 3- and 1.7-fold increase in cell death, as assessed by by Hoechst staining, respectively (p<0.05, n=3 or 4). Similar results were obtained when cell death rates were evaluated by cell enumeration. The ratio of OM/SC cell death in response to serum deprivation was positively correlated with body mass index (r=0.96; p<0.01, n=5). The depot-specific difference in apoptosis susceptibility observed was lost when a stronger apoptotic stimulus (TNFα with cycloheximide) was used. Depot-related differences in apoptotic susceptibility of adipose progenitor cells may influence regional cellular remodelling during adipose tissue expansion and alter metabolic functionality in obesity.

Zfp423 Expression Identifies Committed Preadipocytes and Localizes to Adipose Endothelial and Perivascular Cells

Progress has been made in elucidating the cell-surface phenotype of primary adipose progenitors; however, specific functional markers and distinct molecular signatures of fat depot-specific preadipocytes have remained elusive. In this study, we label committed murine adipose progenitors through expression of GFP from the genetic locus for Zfp423, a gene controlling preadipocyte determination. Selection of GFP-expressing fibroblasts from either subcutaneous or visceral adipose-derived stromal vascular cultures isolates stably committed preadipocytes that undergo robust adipogenesis. Immunohistochemistry for Zfp423-driven GFP expression invivo confirms a perivascular origin of preadipocytes within both white and brown adipose tissues. Interestingly, a small subset of capillary endothelial cells within white and brown fat also express this marker, suggesting a contribution of specialized endothelial cells to the adipose lineage. Zfp423(GFP) mice represent a simple tool for the specific localization and isolation of molecularly defined preadipocytes from distinct adipose tissue depots.

Adipose tissue function and dysfunction: organ cross talk and metabolic risk

OBESITY IS A COMPLEX AND ESCALATING metabolic disorder characterized by a positive disequilibrium between energy intake and energy expenditure. The consequent expansion of the adipose organ, and in particular of visceral fat depots, increases the risk of developing obesity complications such as insulin resistance, type 2 diabetes, atherosclerosis, obstructive sleep apnea, steatohepatitis, and cardio- and cerebrovascular diseases. In this context, several clinical and biochemical elements may act as risk factors for cardiovascular disease, including low high-density lipoprotein cholesterol, high triglycerides, increased concentrations of apolipoprotein B, and small, dense low-density lipoprotein particles, arterial hypertension, hyperglycemia, hyperuricemia, and microalbuminuria. The more risk factors are present in any individual, the higher the risk of transition to diabetes and/or cardiovascular disease (10). The increase in abdominal circumference is the clinical parameter that probably best identifies the risk of clustering other features of the insulin resistance/metabolic syndrome (2) and of predicting overall mortality (8). Recent experimental evidence suggests that adipocytes located in the abdominal region display distinct cellular features compared with adipocytes from other fat depots (5). Consequently, a specific dysfunction of the visceral adipocyte has been proposed as the pathophysiological basis for the negative consequences of abdominal obesity. Although the epidemiological association between fat accumulation and excess risk of diabetes and of cardiovascular disease is striking, the biological mechanisms underlying the adverse impact of adipose tissue remain incompletely defined. Evidently, adipose tissue is not only responsible for storage of energy, but operates as a highly active and dynamic tissue. Adipocytes produce hormones and cytokines, collectively called adipokines, with pleiotropic effects on multiple tissues, leading to fine tuning of fuel utilization, energy homeostasis, and cardiovascular function. It should also be recognized that the functional attitude of visceral and subcutaneous adipocytes is programmed quite early during development and differentiation, due to inherent characteristics of the adipocyte precursors, multipotent cells that are resident in each fat depot and possess defined depot-specific genetic, biochemical, and metabolic features (3, 7, 9, 12, 15). Thus, the biological specificity of the distinct adipose tissue depots may reside in the different biological profile of the resident cells, including the adipocyte precursors.

Protein restriction during early development enhances insulin responsiveness but selectively impairs sensitivity to insulin at low concentrations in white adipose tissue during a later pregnancy

Poor early nutrition may elicit long-term detrimental effects on adult health, including susceptibility to non-insulin-dependent diabetes mellitus. We investigated the impact of moderate maternal protein restriction during pregnancy and lactation on the action of insulin on adipocyte glucose uptake in female offspring during their own pregnancies. Offspring of dams provided with diets containing either 200 g protein/kg or 80 g protein/kg during pregnancy and lactation (termed C and EPR groups respectively) were weaned on to 200 g protein/kg diet at 24 d of age. At 9-12 weeks of age both groups were time-mated and studied at day 19 of gestation. Rates of glucose utilization (assessed using the 2-deoxy-D-[1-3H]glucose technique) measured in five distinct adipose tissue depots (parametrial (PM), mesenteric (MES), perirenal (PR), subcutaneous (s.c.), interscapular (IS)) in vivo in the post-absorptive state were consistently lower in early-protein-restricted (EPR) pregnant rats compared with control (C) pregnant rats. In C pregnant rats, insulin significantly increased glucose utilization only in the IS depot. In contrast, significantly increased glucose utilization rates in response to hyperinsulinaemia were evident in all five adipose-tissue depots of the EPR pregnant group. Consequently, glucose utilization rates in PM and s.c. depots during hyperinsulinaemia were significantly higher in EPR pregnant rats compared with C pregnant rats. Adipocytes were isolated from PM and MES depots to determine whether altered responses to insulin in vivo were retained in vitro. Rates of insulin-stimulated glucose uptake at sub-maximal (15 microU/ml) and maximal (15 mU/ml) insulin concentrations were significantly higher in both MES and PM adipocytes from EPR pregnant rats, but the sensitivity of glucose uptake to insulin at low concentrations was blunted compared with adipocytes from C pregnant rats. The results demonstrate that early protein restriction enhances the capacity for adipocyte glucose uptake at high insulin concentrations, but dampens the response to insulin at low physiological concentrations.

Developmental aspects of the Adipose tissue renin‐angiotensin system: Therapeutic implications

AbstractAdipose tissue possesses considerable growth potential, and excess adipose tissue mass is associated with noninsulin dependent diabetes mellitus (NIDDM). Adipose tissue is a significant source of angiotensinogen, the precursor of angiotensin II (All), a vasoactive peptide with in vitro mitogenic effects. The renin‐angiotensin system remains only partially identified in adipose tissue, however, and knowledge of whether All has a physiologic role in this tissue is dependent in part upon other components of the system being characterized. We have chosen to further investigate aspects of the renin‐angiotensin system in separate adipose tissue depots of rats during growth and development of the tissue. Either epididymal or retroperitoneal adipose tissue was examined in young lean, or adult obese male Sprague‐Dawley rats. Adipose tissue was subjected to collagenase digestion, yielding separate vascular and fat cell fractions. Each fraction was analyzed for angiotensin converting enzyme (ACE) activity and All receptor binding capacity. ACE activity was significantly greater when expressed per gram of adipose tissue in the young lean rats. Vascular and fat cell fractions exhibited All receptors of high affinity, with a greater density of receptors observed in the epididymal adipose tissue fractions. Incubation of adipocytes with exogenous All was associated with the release of prostaglandin into the medium, and analyses of adipocyte cytosol indicated the presence of angiotensinogen. Growing rats given oral losartan, an All receptor antagonist, once daily (15 mg/kg) for 2 weeks exhibited reductions in body weight gain, fat mass, fat cell volume, and All receptor number. These data further document the presence of a peripheral renin‐angiotensin system in anatomically distinct adipose tissue depots at different stages of growth. While the characterization of the effects of All upon adipose tissue development remains incomplete, future investigations with agents affecting the adipocyte renin‐angiotensin system could provide additional information on the role of this system in adipose tissue growth.

Adipocyte blood flow: influence of age, anatomic location, and dietary manipulation.

Adipocyte blood flow in four distinct adipose tissue depots has been measured in conscious, unrestrained, male Sprague-Dawley rats by using the microsphere technique together with cellularity determinations. Blood flow was determined in young rats (90 days old, 387 g mean body wt), spontaneously obese rats (450 days old, 713 g mean body wt), and long-term calorically restricted rats (450 days old, 390 g mean body wt), therefore allowing the comparison of the relative effects of age and fat mass on adipose tissue blood flow. Results of these experiments indicate that while cardiac index remained constant, cardiac output increased in only the obese group, concomitant with increased body fat mass. Spontaneously obese rats exhibited increased adipose tissue depot weight, fat cell lipid, and fat cell size compared with young and restricted groups. Despite significant differences in cell volume, blood flow per cell was remarkably similar between young and obese rats. Long-term caloric restriction, however, was associated with decreased flow per cell. Interdepot comparisons of flow per unit surface area (mm2) or per unit volume (pl) indicate that mesenteric cells receive significantly more blood than cells of the other depots. Our results suggest that adipocyte blood flow is dependent in part on anatomic location, may be further influenced by age or dietary manipulation, and is not a limiting factor in the enlargement of adipocytes during the development of spontaneous obesity.