White Adipose Tissue Growth Research Articles

Impact of Sex on the Therapeutic Efficacy of Rosiglitazone in Modulating White Adipose Tissue Function and Insulin Sensitivity.

Obesity and type 2 diabetes mellitus are global public health issues. Although males show higher obesity and insulin resistance prevalence, current treatments often neglect sex-specific differences. White adipose tissue (WAT) is crucial in preventing lipotoxicity and inflammation and has become a key therapeutic target. Rosiglitazone (RSG), a potent PPARγ agonist, promotes healthy WAT growth and mitochondrial function through MitoNEET modulation. Recent RSG-based strategies specifically target white adipocytes, avoiding side effects. Our aim was to investigate whether sex-specific differences in the insulin-sensitizing effects of RSG exist on WAT during obesity and inflammation. We used Wistar rats of both sexes fed a high-fat diet (HFD, 22.5% fat content) for 16 weeks. Two weeks before sacrifice, a group of HFD-fed rats received RSG treatment (4 mg/kg of body weight per day) within the diet. HFD male rats showed greater insulin resistance, inflammation, mitochondrial dysfunction, and dyslipidemia than females. RSG had more pronounced effects in males, significantly improving insulin sensitivity, fat storage, mitochondrial function, and lipid handling in WAT while reducing ectopic fat deposition and enhancing adiponectin signaling in the liver. Our study suggests a significant sexual dimorphism in the anti-diabetic effects of RSG on WAT, correlating with the severity of metabolic dysfunction.

The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch.

White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We will discuss the interactions of macrophages with other cell partners in WAT including adipose stem cells, adipocytes, and T cells in the context of various microenvironment niches in lean or obese condition. Finally, we highlight how adipose tissue macrophages merge immunity and metabolic changes to govern energy balance for the organism.

309-OR: Adipose RNA N6-Methyladenosine (m6A) Modification Promotes Obesity and Insulin Resistance through Suppressing Lipolysis

Excessive white adipose tissue (WAT) promotes insulin resistance and nonalcoholic fatty liver disease (NAFLD) in obesity; however, the WAT expansion mechanism remains poorly understood. We reported that WAT lipolysis is suppressed in obesity, likely contributing to WAT growth. Adipose triglyceride lipase (Atgl) catalyzes the lipolysis reaction, and its lipolytic activity is increased by phosphorylation and binding to cofactor Cgi58. The sympathetic nervous system activates adipocyte β adrenergic receptor (Adrb)/cAMP/PKA pathway to stimulate lipolysis via Atgl and Cgi58. In this study, we have identified a novel m6A modification of Adrb, Atgl, and Cgi58 transcripts that promotes obesity and metabolic disorders. We found that obesity was associated with increased expression of adipose Mettl3 and Mettl14 and elevated m6A levels in WAT. Mettl14 directly binds to Mettl3 to form a methyltransferase complex that catalyzes m6A on RNA. Insulin also increased Mettl14 expression and m6A levels in adipocytes. We generated adipocyte-specific Mettl14 knockout mice (Mettl14 Δfat) and placed mice on a high fat diet (HFD). Remarkably, Mettl14 Δfat mice, both males and females, were resistant to HFD-induced obesity, insulin resistance, and NAFLD. Adipose Adrb2/3, Atgl, and Cgi58 protein levels were significantly upregulated in Mettl14 Δfat mice and consequently, adipose β adrenergic signaling and lipolysis were significantly higher in Mettl14 Δfat than in Mettl14f/f mice. Mettl14 deficiency dramatically decreased the m6A content of Adrb2/3, Atgl, and Cgi58 transcripts in WAT; strikingly, m6A inhibition markedly increased translational rates of these transcripts in adipocytes. Collectively, these results unravel a previously unrecognized adipose Mettl14/m6A/translation axis that promotes obesity, insulin resistance, and NAFLD by suppressing adipose β adrenergic signaling, lipolysis, and fatty acid oxidation. Disclosure Q.Kang: None. L.Rui: None. D.Ren: None. Funding National Institutes of Health (R01DK130111)

Subcutaneous adipose tissue expansion mechanisms are similar in early and late onset overweight/obesity

Background/objectiveThe development of overweight/obesity associates with alterations in white adipose tissue (WAT) cellularity (fat cell size/number) and lipid metabolism, in particular lipolysis. If these changes differ between early/juvenile (EOO < 18 years of age) or late onset overweight/obesity (LOO) is unknown and was presently examined.Subjects/methodsWe included 439 subjects with validated information on body mass index (BMI) at 18 years of age. Using this information and current BMI, subjects were divided into never overweight/obese (BMI < 25 kg/m2), EOO and LOO. Adipocyte size, number, morphology (size in relation to body fat) and lipolysis were determined in subcutaneous abdominal WAT. Body composition and WAT distribution was assessed by dual-X-ray absorptiometry.ResultsCompared with never overweight/obese, EOO and LOO displayed larger WAT amounts in all examined depots, which in subcutaneous WAT was explained by a combination of increased size and number of fat cells in EOO and LOO. EOO had 40% larger subcutaneous fat mass than LOO (p < 0.0001). Visceral WAT mass, WAT morphology and lipolysis did not differ between EOO and LOO except for minor differences in men between the two obesity groups. On average, the increase in BMI per year was 57% higher in subjects with EOO compared to LOO (p < 0.0001).ConclusionEarly onset overweight/obesity causes a more rapid and pronounced accumulation of subcutaneous WAT than adult onset. However, fat mass expansion measures including WAT cellularity, morphology and fat cell lipolysis do not differ in an important way suggesting that similar mechanisms of WAT growth operate in EOO and LOO.

Sprouty1 regulates gonadal white adipose tissue growth through a PDGFRα/β-Akt pathway

ABSTRACT Expansion of visceral white adipose tissue (vWAT) occurs in response to nutrient excess, and is a risk factor for metabolic disease. SPRY1, a feedback inhibitor of receptor tyrosine kinase (RTK) signaling, is expressed in PDGFRa+ adipocyte progenitor cells (APC) in vivo. Global deficiency of Spry1 in mice results in disproportionate postnatal growth of gonadal WAT (gWAT), while iWAT and BAT were similar in size between Spry1KO and WT mice. Spry1 deficiency increased the number of PDGFRa+ stromal vascular fraction (SVF) cells in gWAT and showed increased proliferation and fibrosis. Spry1KO gWAT had increased collagen deposition and elevated expression of markers of inflammation. In vitro, SPRY1 was transiently down regulated during early adipocyte differentiation of SVF cells, with levels increasing at later stages of differentiation. SPRY1 deficiency enhances PDGF-AA and PDGF-BB induced proliferation of SVF cells. Increased proliferation of SVF from Spry1KO gWAT accompanies an increase in AKT activation. PDGF-AA stimulated a transient down regulation of SPRY1 in wild type SVF, whereas PDGF-BB stimulated a sustained down regulation of SPRY1 in wild type SVF. Collectively, our data suggest that SPRY1 is critical for regulating postnatal growth of gWAT by restraining APC proliferation and differentiation in part by regulation of PDGFRa/b-AKT signaling.

Adrenomedullin has a role in angiogenic effects of resveratrol in adipose tissues of obese female rats.

Obesity is a complex, chronic disease that arises according to the interaction between genetic and environmental factors. The expansion and growth of white adipose tissue (WAT) could be related to angiogenesis. Resveratrol and adrenomedullin (AdM) were used for the inhibition of angiogenesis in metabolically passive WAT for inhibiting the expansion of this tissue, and the activation of angiogenesis in metabolically active brown adipose tissue (BAT) for increasing daily energy consumption as a way of reducing obesity. Rats were divided into eight groups. Four obese groups were fed with a high-fat diet containing 60% fat as energy for three months. After obtaining obesity, 2.5nmol/kg AdM and 10mg/kg resveratrol were treated to experiment groups intraperitoneally (i.p.) every other day for four weeks. AdM and vascular endothelial growth factor A (VEGF-A) mRNA levels were detected with semi-quantitative PCR; protein levels were detected with Western Blotting. AdM and resveratrol are multifactorial molecules, thus, this study has revealed a few novel evidence. The results were distinct in the group and treatment levels. The results showed that resveratrol has a role in angiogenesis in obesity and contributed to AdM production. It is observed that AdM has regulated its expression and increased the effect of resveratrol in WAT. AdM and VEGF-A gene expressions could not be detected in BAT; however, it is suggested that resveratrol may have a pro-angiogenic effect in BAT of obese rats according to the protein levels. AdM also has regulated VEGF-A level according to the metabolic situation of the organism.

Sox9-Meis1 Inactivation Is Required for Adipogenesis, Advancing Pref-1+ to PDGFRα+ Cells

SUMMARYAdipocytes arise from the commitment and differentiation of adipose precursors in white adipose tissue (WAT). In studying adipogenesis, precursor markers, including Pref-1 and PDGFRα, are used to isolate precursors from stromal vascular fractions of WAT, but the relation among the markers is not known. Here, we used the Pref-1 promoter-rtTA system in mice for labeling Pref-1+ cells and for inducible inactivation of the Pref-1 target Sox9. We show the requirement of Sox9 for the maintenance of Pref-1+ proliferative, early precursors. Upon Sox9 inactivation, these Pref-1+ cells become PDGFRα+ cells that express early adipogenic markers. Thus, we show that Pref-1+ cells precede PDGFRα+ cells in the adipogenic pathway and that Sox9 inactivation is required for WAT growth and expansion. Furthermore, we show that in maintaining early adipose precursors, Sox9 activates Meis1, which prevents adipogenic differentiation. Our study also demonstrates the Pref-1 promoter-rtTA system for inducible gene inactivation in early adipose precursor populations.

Transgenerational Effects of High Salt Diet During Gestation

IntroductionThe influence of high salt intake during gestation on the offspring was observed in several studies. It is also known that a phenotype can be transmitted from one generation to the next one without alterations in the DNA sequence. Based on this knowledge, we hypothesized that the effects of high salt ingestion during pregnancy can be transmitted to generations F2 and F3. Therefore, gene expression and DNA methylation of some components of RAS system as well as gene 11beta‐hydroxysteroid dehydrogenase (11βHSD), involved in glucocorticoid conversion, were evaluated.Material and MethodsFemale Wistar rats were fed with normal (N) or hight (H) salt diet during pregnancy. Afterwards, all animals were fed with N, until the third generation. Body and organ mass, gene expression (RT‐qPCR) and methylation (High Resolution Melting – in progress), were evaluated in three generations of males.Resultsdata presented as mean±SEM. TableNo differences between H and N were observed in AT1a, ACE (angiotensin conversion enzyme) and HSD11β2 DNA methylation in the kidney of F1.DiscussionHigh salt intake during pregnancy has a transgenerational effect on kidneys, testis and white adipose tissue growth. The gene expressions that were evaluated were influenced by the maternal dietary salt content in a variable manner in the offspring along three generations.Support or Funding InformationThis study was supported by FAPESP (2012/22415‐5, 2012/22801‐2) Variable \ Generation FI F2 F3 Body weight (g) N 458.8±8.64 492.7±11.03 455.1±11.75 H 438.1±8.54 464.3±7.86* 475.4±8.54 Right kidney mass (g/100g BW) N 0.32±0.004 0.33±0.008 0.33±0.005 H 0.36±0.007* 0.35±0.004* 0.34±0.005* Left kidney mass (g/100g BW) N 0.33±0.007 0.32±0.007 0.33±0.005 H 0.36±0.007* 0.34±0.005* 0.34±0.003* Left testis mass (g/100g BW) N 0.35±0.01 0.36±0.008 0.39±0.001 H 0.39±0.01* 0.39±0.009* 0.36±0.007* Retro peritoneal fat mass (g/100g BW)Kidney gene expression N 0.50±0.10 0.76±0.05 0.68±0.006 H 0.82±0.06* 0.73±0.06* 0.88±0.006* AT1a N 0.82±0.27 1.28±0.39 0.93±0.10 H 1.80±0.43* 1.33±0.24 1.06±0.15 AGT N 0.85±0.21 1.00±0.11 1.60±0.17 H 1.51±0.24 0.87±0.10 0.96±0.23* HSD11β2 N 1.03±0.43 1.03±0.11 0.97±0.16 H 1.65±0.28* 1.33±0.22 1.11±0.18 difference between groups (N vs. H) ‐p≤0.05. Number of animals: F1 (N=9;H=6), F2 (N=12;H=19) and F3 (N=11;H=16). AT1a=angiotensin II receptor 1a; AGT=angiotensinogen.

Dietary protein intake affects expression of genes for lipid metabolism in porcine skeletal muscle in a genotype-dependent manner.

Skeletal muscle is a major site for the oxidation of fatty acids (FA) in mammals, including humans. Using a swine model, we tested the hypothesis that dietary protein intake regulates the expression of key genes for lipid metabolism in skeletal muscle. A total of ninety-six barrows (forty-eight pure-bred Bama mini-pigs (fatty genotype) and forty-eight Landrace pigs (lean genotype)) were fed from 5 weeks of age to market weight. Pigs of fatty or lean genotype were randomly assigned to one of two dietary treatments (low- or adequate-protein diet), with twenty-four individually fed pigs per treatment. Our data showed that dietary protein levels affected the expression of genes involved in the anabolism and catabolism of lipids in the longissimus dorsi and biceps femoris muscles in a genotype-dependent manner. Specifically, Bama mini-pigs had more intramuscular fat, SFA and MUFA, as well as elevated mRNA expression levels of lipogenic genes, compared with Landrace pigs. In contrast, Bama mini-pigs had lower mRNA expression levels of lipolytic genes than Landrace pigs fed an adequate-protein diet in the growing phase. These data are consistent with higher white-fat deposition in Bama mini-pigs than in Landrace pigs. In conclusion, adequate provision of dietary protein (amino acids) plays an important role in regulating the expression of key lipogenic genes, and the growth of white adipose tissue, in a genotype- and tissue-specific manner. These findings have important implications for developing novel dietary strategies in pig production.

Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity.

Excessive accumulation of white adipose tissue (WAT) is the defining characteristic of obesity. WAT mass is composed primarily of mature adipocytes, which are generated through the proliferation and differentiation of adipocyte precursors (APs). While the production of new adipocytes contributes to WAT growth in obesity, little is known about the cellular and molecular mechanisms underlying adipogenesis in vivo. Here, we show that high-fat diet feeding in mice rapidly and transiently induces proliferation of APs within WAT to produce new adipocytes. Importantly, the activation of adipogenesis is specific to the perigonadal visceral depot in male mice, consistent with the patterns of obesogenic WAT growth observed in humans. Additionally, we find that in multiple models of obesity, the activation of APs is dependent upon the phosphoinositde 3-kinase (PI3K)-AKT2 pathway; however, the development of WAT does not require AKT2. These data indicate that developmental and obesogenic adipogenesis are regulated through distinct molecular mechanisms.

Depletion of white adipocyte progenitors induces beige adipocyte differentiation and suppresses obesity development.

Overgrowth of white adipose tissue (WAT) in obesity occurs as a result of adipocyte hypertrophy and hyperplasia. Expansion and renewal of adipocytes relies on proliferation and differentiation of white adipocyte progenitors (WAP); however, the requirement of WAP for obesity development has not been proven. Here, we investigate whether depletion of WAP can be used to prevent WAT expansion. We test this approach by using a hunter-killer peptide designed to induce apoptosis selectively in WAP. We show that targeted WAP cytoablation results in a long-term WAT growth suppression despite increased caloric intake in a mouse diet-induced obesity model. Our data indicate that WAP depletion results in a compensatory population of adipose tissue with beige adipocytes. Consistent with reported thermogenic capacity of beige adipose tissue, WAP-depleted mice display increased energy expenditure. We conclude that targeting of white adipocyte progenitors could be developed as a strategy to sustained modulation of WAT metabolic activity.

Depletion of white adipocyte progenitors suppresses obesity development (LB763)

The study objective is to test a new approach to obesity prevention. Overgrowth of white adipose tissue (WAT) in obesity occurs as a result of adipocyte hypertrophy and hyperplasia. Expansion and renewal of adipocytes relies on proliferation and differentiation of white adipocyte progenitors (WAP), however, the requirement of WAP for obesity development has not been proven. Here, we investigate whether depletion of WAP can be used to prevent WAT expansion. We test this approach by using a hunter‐killer peptide designed to induce apoptosis selectively in WAP. We show that targeted WAP cytoablation results in a long‐term WAT growth suppression despite increased caloric intake in a mouse diet‐induced obesity model. Our data indicate that WAP depletion results in a compensatory beige adipocyte differentiation from an alternative progenitor cell population. Consistent with reported thermogenic capacity of beige adipose tissue, WAP‐depleted mice display increased energy expenditure. We conclude that targeting of adipocyte progenitors could be developed as a strategy to modulate WAT metabolic activity.Grant Funding Source: American Heart Association and Cancer Prevention and Research Institute of Texas

Differential expression of NGF and BDNF in rat adipose depots during early development and adulthood

According to the current paradigm, the white adipose tissue (WAT) not only releases fatty acids, cholesterol, retinoids and other lipids stored in the adipocytes, but also produce and secrete numerous signaling proteins collectively termed adipokines. Among them are various cell growth factors such as nerve growth factor (NGF) and brain-derived growth factor (BDNF). While literature around obesity and its related diseases is abundant, we still do not know how WAT behaves during normal development. In the present study, we explored the expression of NGF and BDNF in the peripancreatic fat tissue (Ppf) and the epididymal fat tissue (Epf ) during a critical period for the metabolic maturation of male Wistar rats. At birth almost no abdominal WAT was observed in the rats. From day 15 to adulthood (2 months), it increased in weight. However, the adipocyte diameter was not different during the first month, compared to adulthood, indicating that the tissue growth in this stage was mostly hypertrophic, while in the second month we also observed hyperplasia of the adipocytes. We measured the production of the neutrophins NGF and BDNF by the abdominal WAT depots. We observed a significant reduction in the expression of NGF in Epf at 28d and two months. However, NGF expression in Ppf remained stable from postnatal 15d to adulthood, except for a nadir at 28d. On the other hand, we failed to detect BDNF during the first 2 months of life in Ppf, but it was expressed at detectable amounts in Epf, peaking at day 20. We do not know how these secretory changes influence the development of the cells and the surrounding tissues. However, in obesity the amount of WAT is increased, and it is necessary to understand the mechanisms of WAT growth in physiological state to identify with the unbalance in this tissue present in obesity. Adipobiology 2013; 5: 39-43.

Liver kinase b1 is required for white adipose tissue growth and differentiation.

White adipose tissue (WAT) is not only a lipogenic and fat storage tissue but also an important endocrine organ that regulates energy homeostasis, lipid metabolism, appetite, fertility, and immune and stress responses. Liver kinase B1 (LKB1), a tumor suppressor, is a key regulator in energy metabolism. However, the role of LKB1 in adipogenesis is unknown. The current study aimed to determine the contributions of LKB1 to adipogenesis in vivo. Using the Fabp4-Cre/loxP system, we generated adipose tissue–specific LKB1 knockout (LKB1ad−/−) mice. LKB1ad−/− mice exhibited a reduced amount of WAT, postnatal growth retardation, and early death before weaning. Further, LKB1 deletion markedly reduced the levels of insulin receptor substrate 1 (IRS1), peroxisome proliferator–activated receptor γ, CCAAT/enhancer-binding protein α, and phosphorylated AMP-activated protein kinase (AMPK). Consistent with these results, overexpression of constitutively active AMPK partially ablated IRS1 degradation in LKB1-deficient cells. LKB1 deletion increased the levels of F-box/WD repeat-containing protein (Fbw) 8, the IRS1 ubiquitination E3 ligase. Silencing of Fbw8 increased IRS1 levels. Finally, promoter analysis and DNA chromatin immunoprecipitation analysis identified three sterol regulatory element (SRE) sites in the Fbw8 promoter, where SRE-binding protein 1c binds and induces the expression of Fbw8. Taken together, these data indicate that LKB1 controls IRS1-dependent adipogenesis via AMPK in WAT.

An Evi1-C/EBPβ Complex Controls Peroxisome Proliferator-Activated Receptor γ2 Gene Expression To Initiate White Fat Cell Differentiation

Fibroblastic preadipocyte cells are recruited to differentiate into new adipocytes during the formation and hyperplastic growth of white adipose tissue. Peroxisome proliferator-activated receptor γ (PPARγ), the master regulator of adipogenesis, is expressed at low levels in preadipocytes, and its levels increase dramatically and rapidly during the differentiation process. However, the mechanisms controlling the dynamic and selective expression of PPARγ in the adipocyte lineage remain largely unknown. We show here that the zinc finger protein Evi1 increases in preadipocytes at the onset of differentiation prior to increases in PPARγ levels. Evi1 expression converts nonadipogenic cells into adipocytes via an increase in the predifferentiation levels of PPARγ2, the adipose-selective isoform of PPARγ. Conversely, loss of Evi1 in preadipocytes blocks the induction of PPARγ2 and suppresses adipocyte differentiation. Evi1 binds with C/EBPβ to regulatory sites in the Pparγ locus at early stages of adipocyte differentiation, coincident with the induction of Pparγ2 expression. These results indicate that Evi1 is a key regulator of adipogenic competency.

Obesity is not linked to increased whole-body mast cell burden in children

Obesity is clearly associated with insulin resistance and chronic low-grade inflammation.1,2 Macrophages appear to be especially important in this relationship because they infiltrate adipose tissue and produce a variety of inflammatory cytokines.1 Exploring the contribution of other immune cells to the development of obesity, Liu et al3 described a role for mast cells in the development of obesity and diabetes in mice. Using genetically modified mice and pharmacologic stabilizers of mast cells, they demonstrated that mast cells and mast cell–mediated protease expression can promote the growth of white adipose tissue.

Subchronic treatment of rats with oxytocin results in improved adipocyte differentiation and increased gene expression of factors involved in adipogenesis

Treatment with thiazolidinediones, insulin-sensitizing drugs, enhances adipogenesis, which may result in unwanted increase in adiposity. Based on the suggested metabolic effects of oxytocin, the aims of the present study were to: (i) determine whether chronic treatment with oxytocin exerts positive effects on white adipose tissue growth without increasing adiposity; (ii) investigate possible mechanisms of action of oxytocin by measuring the level of gene expression of adipogenic factors; and (iii) test the hypothesis that oxytocin's effect on adipose tissue involves specific activation of eukaryotic elongation factor 2 (eEF2). Adult rats were subcutaneously treated with oxytocin (3.6 µg·100 g⁻¹ body weight day⁻¹) via osmotic minipumps for 2 weeks. Adipocytes from epididymal adipose tissue were isolated and their size evaluated by light microscopy. Gene expression of adipogenic and angiogenic factors was determined by real-time PCR and dephosphorylation of eEF2 by immunoblotting. Oxytocin treatment decreased the diameter of adipocytes and increased the epididymal adipose tissue protein content without changing the adipose tissue mass. Increases in fatty acid binding protein, peroxisome proliferator-activated receptor γ, insulin-sensitive glucose transporter 4, leptin and CD31 mRNA levels were noted in the epididymal and/or retroperitoneal fat tissue of oxytocin-treated rats. Oxytocin enhanced the dephosphorylation of eEF2 in the epididymal adipose tissue. The present results demonstrate that subchronic treatment with oxytocin induces adipogenic and angiogenic effects and that the eEF2 signalling pathway is involved in these effects of oxytocin on adipose tissue in vivo. These findings are likely to motivate further research and indicate new approaches for modulating adipose tissue morphology and metabolism.

Beneficial effects of l-arginine on reducing obesity: potential mechanisms and important implications for human health

Over the past 20 years, growing interest in the biochemistry, nutrition, and pharmacology of L-arginine has led to extensive studies to explore its nutritional and therapeutic roles in treating and preventing human metabolic disorders. Emerging evidence shows that dietary L-arginine supplementation reduces adiposity in genetically obese rats, diet-induced obese rats, finishing pigs, and obese human subjects with Type-2 diabetes mellitus. The mechanisms responsible for the beneficial effects of L-arginine are likely complex, but ultimately involve altering the balance of energy intake and expenditure in favor of fat loss or reduced growth of white adipose tissue. Recent studies indicate that L-arginine supplementation stimulates mitochondrial biogenesis and brown adipose tissue development possibly through the enhanced synthesis of cell-signaling molecules (e.g., nitric oxide, carbon monoxide, polyamines, cGMP, and cAMP) as well as the increased expression of genes that promote whole-body oxidation of energy substrates (e.g., glucose and fatty acids) Thus, L-arginine holds great promise as a safe and cost-effective nutrient to reduce adiposity, increase muscle mass, and improve the metabolic profile in animals and humans.

Thematic review series: Adipocyte Biology. Sympathetic and sensory innervation of white adipose tissue

During our study of the reversal of seasonal obesity in Siberian hamsters, we found an interaction between receptors for the pineal hormone melatonin and the sympathetic nervous system (SNS) outflow from brain to white adipose tissue (WAT). This ultimately led us and others to conclude that the SNS innervation of WAT is the primary initiator of lipid mobilization in these as well as other animals, including humans. There is strong neurochemical (norepinephrine turnover), neuroanatomical (viral tract tracing), and functional (sympathetic denervation-induced blockade of lipolysis) evidence for the role of the SNS in lipid mobilization. Recent findings suggest the presence of WAT sensory innervation based on strong neuroanatomical (viral tract tracing, immunohistochemical markers of sensory nerves) and suggestive functional (capsaicin sensory denervation-induced WAT growth) evidence, the latter implying a role in conveying adiposity information to the brain. By contrast, parasympathetic nervous system innervation of WAT is characterized by largely negative neuroanatomical evidence (viral tract tracing, immunohistochemical and biochemical markers of parasympathetic nerves). Functional evidence (intraneural stimulation and in situ microdialysis) for the role of the SNS innervation in lipid mobilization in human WAT is convincing, with some controversy regarding the level of sympathetic nerve activity in human obesity.

Reply to Kreier and Buijs: no sympathy for the claim of parasympathetic innervation of white adipose tissue

to the editor: Kreier and Buijs ([16][1]) have questioned our work ([14][2]) demonstrating the lack of parasympathetic nervous system (PSNS) innervation of white adipose tissue (WAT) in laboratory rats and mice, as well as in Siberian hamsters. We appreciate the opportunity to clarify and extend our