White Adipose Tissue Depots Research Articles

CRTC1 Maintains Metabolic Homeostasis and Protects Against Partial Lipodystrophy & Insulin Resistance by Regulating Diet‐Responsive White Adipose Tissue Remodeling

Humans evolved the ability to store lipid in specialized tissue called adipose to support survival. Adipose provides an energy depot that can be quickly mobilized in response to acute stress (fight‐or‐flight), for reproduction and during extended fasting. Defects in white adipose tissue (WAT) function, and inability of the WAT depots to expand in the context of overnutrition, will lead to ectopic lipid accumulation in the muscle and liver triggering serious metabolic diseases such as type 2 diabetes (T2D).Our data demonstrate that CREB Regulated Transcription Coactivator 1 (CRTC1) gene function is important in maintaining metabolic fitness. CRTC1 is expressed primarily in the hypothalamus where it controls satiety in response to cAMP and Ca2+ signals. Recent studies identified small nucleotide polymorphisms (SNPs) in the human gene locus CRTC1 that correlate with decreased adiposity in the context of obesity, indicating that CRTC1 may play an important role in adipose function. Here, we describe a previously unknown role of CRTC1 in the regulation of epididymal WAT (eWAT) expansion in response to high fat diet (HFD).Basal CRTC1 protein expression in eWAT is low compared to that in the brain, yet specifically increased in eWAT in response to HFD. Loss of CRTC1 by whole‐body germline knockout (CRTC1 KO mice), acute antisense oligonucleotide knockdown in WAT (CRTC1 ASO mice), and tissue‐specific germline knockout in adipose tissue (CRTC1 AKO mice) results in impaired HFD‐responsive eWAT expansion, observed as a ~50% decrease in eWAT size. Diminished capacity for eWAT expansion coincides with elevated lipid accumulation in liver and muscle, hyperglycemia, hyperinsulinemia and glucose intolerance in these animals relative to wildtype or control.CRTC1 knockdown by adenoviral shRNA decreased glucose uptake, increased lipolysis and impeded expression of the key adipogenesis marker PPARγ in differentiated 3T3‐L1 adipocytes. Animal models with decreased CRTC1 expression (CRTC1 KO, ASO and AKO) also exhibited decreased PPARγ expression in eWAT but only on HFD, suggesting that CRTC1 is required for diet‐responsive eWAT remodeling and for maintaining a differentiated state in adipocytes. Supportive of this hypothesis, we observed significantly decreased eWAT FGF1 mRNA expression, plasma FGF1 and WAT FGF1 levels in HFD‐fed animal models of CRTC1 loss relative to control. FGF1 plays a major role in eWAT remodeling and expansion in response to diet: our data indicate that CRTC1 is required for HFD‐mediated upregulation of FGF1. Together, our findings reveal a regulatory axis that is essential for eWAT remodeling and expansion, and that leads to ectopic lipid deposition and insulin resistance when perturbed. Understanding how CRTC1 regulates FGF1 and impacts the PPARγ pathway in eWAT will provide important insights into adipocyte function and into how eWAT expansion is modulated to maintain metabolic homeostasis, allowing identification of new potential targets to treat diseases such as T2D.Support or Funding InformationLife Science Research Foundation Fellowship, Sponsor: Gilead Sciences Inc.; R01 DK083834, PI: Marc Montminy

Molecular Mechanisms of P311 on White Adipogenesis

BackgroundThe obesity epidemic is a constant and chronic detriment to US as well as global health outcomes. Two‐thirds of the US population is either overweight or obese, and obesity can be linked to many chronic diseases, including diabetes mellitus, cardiovascular diseases, stroke and cancer. Diet and exercise remains the primary therapeutic approaches, but still obesity (40% of US adult population) incidence and prevalence continues to rise, prompting the development of new interventions. P311 is an 8 kDa protein shown to induce adipogenesis in an in vitro 3T3‐L1 cell culture model (Nunez et al. 2019). In the current study, we investigated the molecular mechanisms of P311 in white adipocyte biology.MethodsBoth male and female C57BL/6 control mice and P311 knockout (KO) mice were used for this study. Adipocytes were isolated from individual white adipose tissue depots and adipocyte number and size were quantified using LipidTox staining followed by Guava EasyCyte analysis. Additionally adipocyte cellular functions of P311 like apoptosis, lipophagy and adipose tissue macrophage numbers were verified in P311 KOs and compared with wild type control mice. Real‐time PCR, western blot and immunohistology studies were conducted as described by Badri et al. (2013) and Nunez et al. (2019)ResultsP311 was expressed in murine gonadal and subcutaneous white adipose tissue. White adipocytes isolated from 4‐month‐old mice had significantly higher levels of P311 compared to adipocytes isolated from the white subcutaneous adipose tissue of 1‐month‐old mice. However, progenitor cells (stromal vascular fraction) showed no (basal) expression of P311. P311 KO mice showed decreased PPARγ2 expression. P311 KO mice did not differ from wild type mice in subcutaneous or gonadal white adipose tissue weights, but they had fewer and enlarged adipocytes. Further, P311 KOs also showed decreased apoptosis and lipophagy along with decreased adipocyte macrophage numbers and browning of white adipose tissue. In addition, adult human visceral adipose tissue also showed the expression of P311 in adipocytes implicating a translational role for P311 in adipogenesis and obesity.ConclusionsP311 plays a key role in white adipogenesis and browning of WAT partly through modulating PPARγ2 and also by regulating adipocyte cellular processes including adipocyte apoptosis, lipophagy, browning and macrophage numbers.Support or Funding Information• 2019 Medical Student Summer Research and Public Health Experience (Morehouse School of Medicine)• NIMHD/NIH grant funding through S21MD000101 (to Morehouse School of Medicine)• U54MD008621 (Hampton University, Hampton, VA)

Characterization of different adipose depots in fattened buffalo: histological features and expression profiling of adipocyte markers.

Adipose tissue (AT) is a multi-depot organ in mammals. AT from various depots differs in composition and function. Revealing the composition feature of AT depots will provide valuable information for further research on the development and fat deposition patterns in buffalo. This study explored the cellular morphology and gene expression profiles of brown and beige markers in seven AT depots of fattened buffalo: three subcutaneous depots (back, sternum, and inguinal) and four visceral depots (perirenal, mesenteric, pericardial, and omental). Histological results showed unilocular adipocytes in all seven AT depots. Uncoupling protein 1 (UCP1) mRNA, a brown and beige adipocyte gene, was detected in all depots with the highest level in VAT depots, and a limited number of UCP1-positive unilocular adipocytes were observed in the three VAT depots. The mRNAs of PPARG coactivator 1 alpha (PGC1 ) and transmembrane protein 26 (TMEM26), brown or beige adipocyte markers, were identified in all seven depots and were mainly expressed in VAT depots. However, the mRNA of zinc finger protein of the cerebellum 1 (ZIC1), a brown adipocyte-specific marker, was almost undetectable. Our results demonstrated that all seven AT depots are white adipose tissue (WAT), with potential function of non-shivering thermogenesis in fattened buffalo. Beige adipocytes are more active in VAT depots than in WAT depots. These results improve our knowledge on the feature of different adipose tissue depots in buffalo, which will be useful for the research of fat deposition.

Relative expression and regulation by short-term fasting of lysophosphatidic acid receptors and autotaxin in white and brown adipose tissue depots.

Lysophosphatidic acid (lysoPtdOH) levels have previously been reported to decrease in rodents with short-term fasting. We investigated whether a 16 h fast would change expression of autotaxin, the predominant phospholipase D responsible for adipose-derived lysoPtdOH synthesis, or any of the lysophosphatidic acid receptors (1-6) in four white adipose tissue (WAT) depots and interscapular brown adipose tissue (BAT) in male C57Bl/6J mice fed ad libitum, or fasted for 16 h. Aside from small inductions of Lpar1 in epididymal WAT and Lpar2 in epididymal and inguinal WAT, no significant changes were observed in expression of the Lpar family members, or autotaxin in perirenal, retroperitoneal, epididymal, or inguinal WAT or BAT with fasting. Comparison of the relative expression of Lpar1-6 in various depots showed that Lpar6 was the predominant Lpar in both WAT and BAT, and suggests that further work on the adipose-specific role of Lpar6 is warranted.

Characterization of brown adipose tissue (BAT) in polycystic ovary syndrome (PCOS) patients by Z-Spectral Imaging (ZSI)

PurposeTo characterize brown adipose tissue (BAT) in polycystic ovary syndrome (PCOS) patients in comparison to healthy subjects using Z-spectral imaging (ZSI). MethodZSI data were collected on 19 normal control females (NCF), 17 males (NCM), and 13 PCOS patients. By fitting to multiple Lorentzian functions, ZSI provides fat-water fraction (FWF) of tissue in the supraclavicular area that can be used to differentiate between white adipose tissue (WAT), BAT, and muscle. The fraction of BAT over the total fat depot (BATf) and the average FWF in BAT or FWF(BAT) were then computed, reflecting relative BAT mass and BAT metabolism respectively. The parameters were compared among the three groups, and the correlations to Body Mass Index (BMI) were also quantified. ResultsThere was an inverse correlation between BATf and BMI in normal subjects. The BATf of the PCOS group was significantly smaller than the NCF (P < 0.001). On the other hand, FWF(BAT) correlated linearly with BMI in healthy subjects. The PCOS group had higher FWF(BAT) than the NCF group (P < 0.001). ConclusionsNormal subjects with higher BMI show less BATf and have increased FWF(BAT), indicating relatively higher level of metabolic passive WAT depot and relatively reduced metabolism in their BAT depots. PCOS patients have the least BATf and the highest FWF(BAT), suggesting decreased BAT mass and function in PCOS. Novel imaging technique with ZSI for the characterization of BAT mass and function in PCOS may help to monitor treatment responses of PCOS therapies.

Proglucagon-Derived Peptides, Glucose-Dependent Insulinotropic Polypeptide, and Dipeptidyl Peptidase-4-Mechanisms of Action in Adipose Tissue.

Proglucagon-derived peptides (PGDPs) and related gut hormones exemplified by glucose-dependent insulinotropic polypeptide (GIP) regulate energy disposal and storage through actions on metabolically sensitive organs, including adipose tissue. The actions of glucagon, glucagon-like peptide (GLP)-1, GLP-2, GIP, and their rate-limiting enzyme dipeptidyl peptidase-4, include direct and indirect regulation of islet hormone secretion, food intake, body weight, all contributing to control of white and brown adipose tissue activity. Moreover, agents mimicking actions of these peptides are in use for the therapy of metabolic disorders with disordered energy homeostasis such as diabetes, obesity, and intestinal failure. Here we highlight current concepts and mechanisms for direct and indirect actions of these peptides on adipose tissue depots. The available data highlight the importance of indirect peptide actions for control of adipose tissue biology, consistent with the very low level of endogenous peptide receptor expression within white and brown adipose tissue depots. Finally, we discuss limitations and challenges for the interpretation of available experimental observations, coupled to identification of enduring concepts supported by more robust evidence.

MiRNAs and Novel Food Compounds Related to the Browning Process.

Obesity prevalence is rapidly increasing worldwide. With the discovery of brown adipose tissue (BAT) in adult humans, BAT activation has emerged as a potential strategy for increasing energy expenditure. Recently, the presence of a third type of fat, referred to as beige or brite (brown in white), has been recognized to be present in certain kinds of white adipose tissue (WAT) depots. It has been suggested that WAT can undergo the process of browning in response to stimuli that induce and enhance the expression of thermogenesis: a metabolic feature typically associated with BAT. MicroRNAs (miRNAs) are small transcriptional regulators that control gene expression in a variety of tissues, including WAT and BAT. Likewise, it was shown that several food compounds could influence miRNAs associated with browning, thus, potentially contributing to the management of excessive adipose tissue accumulation (obesity) through specific nutritional and dietetic approaches. Therefore, this has created significant excitement towards the development of a promising dietary strategy to promote browning/beiging in WAT to potentially contribute to combat the growing epidemic of obesity. For this reason, we summarize the current knowledge about miRNAs and food compounds that could be applied in promoting adipose browning, as well as the cellular mechanisms involved.

Reactive oxygen species-dependent regulation of pyruvate dehydrogenase kinase-4 in white adipose tissue.

Reactive oxygen species (ROS) are important signaling molecules mediating the exercise-induced adaptations in skeletal muscle. Acute exercise also drives the expression of genes involved in reesterification and glyceroneogenesis in white adipose tissue (WAT), but whether ROS play any role in this effect has not been explored. We speculated that exercise-induced ROS would regulate acute exercise-induced responses in WAT. To address this question, we utilized various models to alter redox signaling in WAT. We examined basal and exercise-induced gene expression in a genetically modified mouse model of reduced mitochondrial ROS emission [mitochondrial catalase overexpression (MCAT)]. Additionally, H2O2, various antioxidants, and the β3-adrenergic receptor agonist CL316243 were used to assess gene expression in white adipose tissue culture. MCAT mice have reduced ROS emission from WAT, enlarged WAT depots and adipocytes, and greater pyruvate dehydrogenase kinase-4 (Pdk4) gene expression. In WAT culture, H2O2 reduced glyceroneogenic gene expression. In wild-type mice, acute exercise induced dramatic but transient increases in Pdk4 and phosphoenolpyruvate carboxykinase (Pck1) mRNA in both subcutaneous inguinal WAT and epididymal WAT depots, which was almost completely absent in MCAT mice. Furthermore, the induction of Pdk4 and Pck1 in WAT culture by CL316243 was markedly reduced in the presence of antioxidants N-acetyl-cysteine or vitamin E. Genetic and nutritional approaches that attenuate redox signaling prevent exercise- and β-agonist-induced gene expression within WAT. Combined, these data suggest that ROS represent important mediators of gene expression within WAT.

Aerobic exercise modulates cardiac NAD(P)H oxidase and the NRF2/KEAP1 pathway in a mouse model of chronic fructose consumption.

The present study investigated the effects of exercise on the cardiac nuclear factor (erythroid-derived 2) factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1) pathway in an experimental model of chronic fructose consumption. Male C57BL/6 mice were assigned to Control, Fructose (20% fructose in drinking water), Exercise (treadmill exercise at moderate intensity), and Fructose + Exercise groups (n = 10). After 12 wk, the energy intake and body weight in the groups were similar. Maximum exercise testing, resting energy expenditure, resting oxygen consumption, and carbon dioxide production increased in the exercise groups (Exercise and Fructose + Exercise vs. Control and Fructose groups, P < 0.05). Chronic fructose intake induced circulating hypercholesterolemia, hypertriglyceridemia, and hyperleptinemia and increased white adipose tissue depots, with no changes in blood pressure. This metabolic environment increased circulating IL-6, IL-1β, IL-10, cardiac hypertrophy, and cardiac NF-κB-p65 and TNF-α expression, which were reduced by exercise (P < 0.05). Cardiac ANG II type 1 receptor and NAD(P)H oxidase 2 (NOX2) were increased by fructose intake and exercise decreased this response (P < 0.05). Exercise increased the cardiac expression of the NRF2-to-KEAP1 ratio and phase II antioxidants in fructose-fed mice (P < 0.05). NOX4, glutathione reductase, and catalase protein expression were similar between the groups. These findings suggest that exercise confers modulatory cardiac effects, improving antioxidant defenses through the NRF2/KEAP1 pathway and decreasing oxidative stress, representing a potential nonpharmacological approach to protect against fructose-induced cardiometabolic diseases.NEW & NOTEWORTHY This is the first study to evaluate the cardiac modulation of NAD(P)H oxidase (NOX), the NRF2/Kelch-like ECH-associated protein 1 pathway (KEAP), and the thioredoxin (TRX1) system through exercise in the presence of moderate fructose intake. We demonstrated a novel mechanism by which exercise improves cardiac antioxidant defenses in an experimental model of chronic fructose intake, which involves NRF2-to-KEAP1 ratio modulation, enhancing the local phase II antioxidants hemoxygenase-1, thioredoxin reductase (TXNRD1), and peroxiredoxin1B (PDRX1), and inhibiting cardiac NOX2 overexpression.

Thermogenic crosstalk occurs between adipocytes from different species

Visceral obesity increases risks for all-cause mortality worldwide. A small population of thermogenic adipocytes expressing uncoupling protein-1 (Ucp1) regulates energy dissipation in white adipose tissue (WAT) depots. Thermogenic adipocytes subsets decrease obesity in mice, but their efficacy has not been tested in obese large animals. Here we enclosed murine subcutaneous adipocytes with and without engineered thermogenic response in biocompatible microcapsules and implanted them into the left and right side of the visceral falciform depot in six obese dogs. After 28 days of treatment, dogs have markedly reduced waist circumference, body weight, and fat mass. Ucp1 expression in canine WAT was increased at sites implanted with thermogenic vs. wild type murine adipocytes. This site-specific thermogenic remodeling of canine tissue by thermogenic murine adipocytes suggests evolutionary conserved paracrine regulation of energy dissipation across species. These findings have translational potential aimed to reduce deleterious WAT depots in humans and pets.

Memory impairments and increased GFAP expression in hippocampal astrocytes following hypercaloric diet in rats.

Hypothalamic inflammation and glial fibrillary acidic protein (GFAP) overexpression in astrocytes are well described in obese animals, as are some cognitive and memory deficits. As the hippocampus plays important roles in the consolidation of information, this investigation aimed to observe the memory function and the astrocyte expression of GFAP in the hippocampus of rats that received either a hypercaloric or a normocaloric diet. Adult male Wistar rats received a high-fat (cafeteria) or a standard diet for 60 days. On the 61st day, the rats were submitted to the novel object recognition (NOR) test at three and 24 hours after the first contact with objects, to assess short-term and long-term memory, respectively. Thereafter, the rats were euthanized and their brains were collected for GFAP immunohistochemical investigation in the hippocampus (CA1, CA2, CA3 areas) and hypothalamus (periventricular and arcuate nuclei). Astrocytic reactivity was assessed by morphometry. Different white adipose tissue depots and brown adipose tissue were weighed to calculate the adiposity index. The hypercaloric diet increased body weight gain, adiposity index, white adipose tissue weight (epididymal, subcutaneous and retroperitoneal) and brown adipose tissue weight. Rats fed with the hypercaloric diet showed short-term and long-term memory impairments in the NOR test, as well as increased GFAP expression in astrocytes from all analyzed hypothalamic and hippocampal areas. This astrogliosis suggests that the neuroinflammatory response also occurs in the hippocampus and may be involved in the memory losses observed in obese/overweight animals.

Maturation of White Adipose Tissue Function in C57BL/6j Mice From Weaning to Young Adulthood.

White adipose tissue (WAT) distribution and WAT mitochondrial function contribute to total body metabolic health throughout life. Nutritional interventions starting in the postweaning period may impact later life WAT health and function. We therefore assessed changes in mitochondrial density and function markers in WAT depots of young mice. Inguinal (ING), epididymal (EPI) and retroperitoneal (RP) WAT of 21, 42 and 98 days old C57BL/6j mice was collected. Mitochondrial density [citrate synthase (CS), mtDNA] and function [subunits of oxidative phosphorylation complexes (OXPHOS)] markers were analyzed, together with gene expression of browning markers (Ucp1, Cidea). mRNA of ING WAT of 21 and 98 old mice was sequenced to further investigate functional changes of the mitochondria and alterations in cell populations. CS levels decreased significantly over time in all depots. ING showed most pronounced changes, including significantly decreased levels of OXPHOS complex I, II, and III subunits and gene expression of Ucp1 (PN21-42 and PN42-98) and Cidea (PN42-98). White adipocyte markers were higher at PN98 in ING WAT. Analyses of RNA sequence data showed that the mitochondrial functional profile changed over time from “growth-supporting” mitochondria focused on ATP production (and dissipation), to more steady-state mitochondria with more diverse functions and higher biosynthesis. Mitochondrial density and energy metabolism markers declined in all three depots over time after weaning. This was most pronounced in ING WAT and associated with reduced browning markers, increased whitening and an altered metabolism. In particular the PN21-42 period may provide a time window to study mitochondrial adaptation and effects of nutritional exposures relevant for later life metabolic health.

ANGIOTENSIN II INDUCES UCP1 IN ADIPOSE TISSUE OF AN EXPERIMENTAL MODEL OF CARDIO-RENAL CACHEXIA

Objective: Cachexia is a severe complication of advanced heart failure and chronic kidney disease. We previously reported that high dose Angiotensin II infusion in rats determined body weight reduction, prevented by an AT-1 receptor blocker treatment and beta-adrenergic non selective antagonism. The possible role of Ang II on UCP1 in white and brown adipose tissue, as a possible mechanism, was investigated in this study. Design and method: Male Sprague-Dawley rats, were implanted subcutaneously in the dorsal region with osmotic minipumps delivering Ang-II at high doses (525 ng/Kg/min) for 12 days to mimic heart failure and the development of cachexia. Five concurrent groups of rats were evaluated: 1) vehicle–infused rats (CTR-rat, n = 9); 2) Ang-II infused rats (n = 7); Ang- II rats receiving by oral gavage 2 days before minipump implantation until the 12th day of Ang-II infusion, either 3) bisoprolol (BIS,β1-adrenergic antagonist, 35 mg/Kg/day, n = 5), or 4) carvedilol (CVD,α1-non-selective-β1,2,3-adrenergic blocker, 90 mg/kg/day, n = 5) or 5) bupranolol (BPR,β3-antagonist, 200 mg/day/kg, n = 4). White adipose tissue (WATs) from retroperitoneal (RWAT), epidydimal (EWAT), dorsal (DWAT) and brown interscapular (IBAT) depot were withdrawn in order to determine UCP1 mRNA expression, norepinephrine tissue level (TNE) and tyrosine hydroxylase activity (THA) Results: THA and TNE were higher in Ang-II infused rats in all the white adipose tissue depots analyzed. CVD prevented TNE increase in all WATs, while BPR and BIS were effective in RWAT and EWAT but not DWAT. All the three beta adrenergic blocker treatments significantly reduced THA increased activity related to Ang-II infusion in all the WATs. UCP1 mRNA was increased in IBAT (+39%, p < 0.05) of Ang II-infused rat, significantly prevented by CVD and BPR but not by BIS. UCP1 was also increased in all the three WATs of Ang-II infused rats, with all the three beta blockers able to reduce the effect in RWAT and DWAT. No effect of beta-blockers treatment was observed in EWAT. Conclusions: High dose angiotensin II infusion determined an increase in UCP1 trascription in brown and white adipose tissue in rats. CVD and BPR were able to prevent UCP1 increase in brown and white adipose tissue more than beta-1 selective antagonist BIS.

Activation of NPRs and UCP1-independent pathway following CB1R antagonist treatment is associated with adipose tissue beiging in fat-fed male dogs.

CB1 receptor (CB1R) antagonism improves the deleterious effects of a high-fat diet (HFD) by reducing body fat mass and adipocyte cell size. Previous studies demonstrated that the beneficial effects of the CB1R antagonist rimonabant (RIM) in white adipose tissue (WAT) are partially due to an increase of mitochondria numbers and upregulation thermogenesis markers, suggesting an induction of WAT beiging. However, the molecular mechanism by which CB1R antagonism induces weight loss and WAT beiging is unclear. In this study, we probed for genes associated with beiging and explored longitudinal molecular mechanisms by which the beiging process occurs. HFD dogs received either RIM (HFD+RIM) or placebo (PL) (HFD+PL) for 16 wk. Several genes involved in beiging were increased in HFD+RIM compared with pre-fat, HFD, and HFD+PL. We evaluated lipolysis and its regulators including natriuretic peptide (NP) and its receptors (NPRs), β-1 and β-3 adrenergic receptor (β1R, β3R) genes. These genes were increased in WAT depots, accompanied by an increase in lipolysis in HFD+RIM. In addition, RIM decreased markers of inflammation and increased adiponectin receptors in WAT. We observed a small but significant increase in UCP1; therefore, we evaluated the newly discovered UCP1-independent thermogenesis pathway. We confirmed that SERCA2b and RYR2, the two key genes involved in this pathway, were upregulated in the WAT. Our data suggest that the upregulation of NPRs, β-1R and β-3R, lipolysis, and SERCA2b and RYR2 may be one of the mechanisms by which RIM promotes beiging and overall the improvement of metabolic homeostasis induced by RIM.

Decreased liver triglyceride content in adult rats exposed to protein restriction during gestation and lactation: roles of hepatic lipogenesis and lipid utilization in muscle and adipose tissue.

Protein restriction throughout pregnancy and lactation reduces liver triglyceride (TG) content in adult male rat offspring. The study determined the contribution of hepatic lipogenesis to the reduction in liver TG content. Rats received either control or protein-restricted diets throughout pregnancy and lactation. Offspring were sacrificed on day 65. Hepatic fatty acid uptake and de novo fatty acid and TG biosynthesis were similar between control and low-protein (LP) offspring. These results indicate that hepatic lipogenesis cannot mediate the decrease in liver TG content in LP offspring. We then determined whether increased lipid utilization in adipose tissue and muscle was responsible for the decrease in liver TG content. There was suggestive evidence of increased sympathetic nervous system tone in epididymal adipose tissue of LP offspring that increased fatty acid uptake, TG lipolysis, and utilization of fatty acids in mitochondrial thermogenesis. Measurement of similar parameters demonstrated that such alterations do not occur in gastrocnemius muscle, another major lipid-utilizing tissue. Our results suggest that the decrease in liver TG content in LP offspring is likely due to increased diversion of fatty acids to white and brown adipose tissue depots and their enhanced utilization to fuel mitochondrial thermogenesis.

Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications.

Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence is rising worldwide. White adipose tissue (WAT) has a crucial role in regulating systemic energy homeostasis. Adipose tissue expands by a combination of an increase in adipocyte size (hypertrophy) and number (hyperplasia). The recruitment and differentiation of adipose precursor cells in the subcutaneous adipose tissue (SAT), rather than merely inflating the cells, would be protective from the obesity-associated metabolic complications. In metabolically unhealthy obesity, the storage capacity of SAT, the largest WAT depot, is limited, and further caloric overload leads to the fat accumulation in ectopic tissues (e.g., liver, skeletal muscle, and heart) and in the visceral adipose depots, an event commonly defined as “lipotoxicity.” Excessive ectopic lipid accumulation leads to local inflammation and insulin resistance (IR). Indeed, overnutrition triggers uncontrolled inflammatory responses in WAT, leading to chronic low-grade inflammation, therefore fostering the progression of IR. This review summarizes the current knowledge on WAT dysfunction in obesity and its associated metabolic abnormalities, such as IR. A better understanding of the mechanisms regulating adipose tissue expansion in obesity is required for the development of future therapeutic approaches in obesity-associated metabolic complications.

Adipose tissue browning in mice and humans

In the midst of an obesity epidemic, the promotion of brown adipose tissue (BAT) function and the browning of white adipose tissue (WAT) have emerged as promising therapeutic targets to increase energy expenditure and counteract weight gain. Despite the fact that the thermogenic potential of bone fide BAT in rodents is several orders of magnitudes higher than white fat containing brite/beige adipocytes, WAT browning represents a particularly intriguing concept in humans given the extreme amount of excess WAT in obese individuals. In addition, the clear distinction between classic brown and beige fat that has been proposed in mice does not exist in humans. In fact, studies of human BAT biopsies found controversial results suggesting both classic brown and beige characteristics. Irrespective of the true ‘color’, accumulating evidence suggests the induction of thermogenic adipocytes in human WAT depots in response to specific stimuli, highlighting that WAT browning may occur in both, mice and humans. These observations also emphasize the great plasticity of human fat depots and raise important questions about the metabolic properties of thermogenically active adipose tissue in humans and the potential therapeutic implications. We will first review the cellular and molecular aspects of selected adipose tissue browning concepts that have been identified in mouse models with emphasis on neuronal factors, the microbiome, immune cells and several hormones. We will also summarize the evidence for adipose tissue browning in humans including some experimental pharmacologic approaches.

Stromal cells maintain immune cell homeostasis in adipose tissue via production of interleukin-33.

Obesity is driven by chronic low-grade inflammation resulting from dysregulated immune cell accumulation and function in white adipose tissue (WAT). Interleukin-33 (IL-33) is a key cytokine that controls innate and adaptive immune cell activity and immune homeostasis in WAT, although the sources of IL-33 have remained controversial. Here, we show that WAT-resident mesenchyme-derived stromal cells are the dominant producers of IL-33. Adipose stem and progenitor cells (ASPCs) produced IL-33 in all WAT depots, whereas mesothelial cells served as an additional source of IL-33 in visceral WAT. ASPC-derived IL-33 promoted a regulatory circuit that maintained an immune tone in WAT via the induction of group 2 innate lymphoid cell-derived type 2 cytokines and maintenance of eosinophils, whereas mesothelial IL-33 also acted as an alarmin by inducing peritoneal immune response upon infection. Together, these data reveal a previously unrecognized regulatory network between tissue-resident progenitor cells and innate lymphoid cells that maintains immune homeostasis in adipose tissue.

Gastrointestinal capacity, gut hormones and appetite change during rat pregnancy and lactation.

Pregnancy and lactation increase maternal appetite and adiposity, which in humans can lead to long-term body mass retention. Previous rat reproduction studies suggest that appetite-inhibiting gut hormone, peptide-YY (PYY), is elevated, despite hyperphagia also that gastrointestinal size increases. The present study characterised changes in orexigenic (appetite-stimulating) ghrelin and anorexigenic (appetite-inhibiting) PYY and glucagon-like peptide-1 (GLP-1), and gastrointestinal architecture during pregnancy and lactation, in matched fed and fasted plasma and gut tissue samples taken during the dark phase. Enteroendocrine cells were immunolabelled, and gut masses and lengths were measured. Fasted plasma ghrelin reduced during pregnancy: it was lowest by day 18, recovered to control values at parturition, then increased by the end of lactation. Ghrelin-immunoreactive stomach cells and stomach ghrelin concentrations were highest at birth, prior to the onset of lactation-associated hyperphagia. Plasma fed GLP-1 concentrations were elevated during pregnancy, and together with higher colon concentrations of PYY and GLP-1 during early lactation, they were associated with gastrointestinal tissue expansion, not satiety. Body mass increased during lactation, whereas white adipose tissue depots depleted. Extensive gut remodelling coincided with elevated colon concentrations of PYY and GLP-1. Modifications included stomach and caecum expansion, and duodenal, ascending and descending colon circumference increases, all peaking by day 10 of lactation; increased intestinal masses and lengths peaking at lactation day 10 for small intestine and lactation day 25 for large intestine. If these physical tissue increases persist post-partum, they could accelerate future nutrient assimilation and storage in dams, and may contribute to increased obesity risk.

Effects of hypothyroidism on the mesenteric and omental adipose tissue in rats

To characterize the influence of hypothyroidism on the endocrine activity of mesenteric and omental adipose tissue (MOAT) and the peripheral regulation of energy balance (EB) in rats, we analyzed food intake (FI); basal metabolic rate (BMR); locomotor activity; body weight (BW); serum hormone concentrations and the expression of their receptors in MOAT. We evaluated the morphology and differentiation of adipocytes. Hypothyroidism decreased FI, BMR and BW. The percentage of visceral white adipose tissue (WAT) depots and the morphology of adipocytes were similar to euthyroid rats. Serum leptin and adiponectin expression in MOAT were altered by hypothyroidism. The expression of Perilipin 1, HSL, UCP1 and PRDM16 was significantly lower in MOAT of hypothyroid animals. Hypothyroidism in rats leads to a compensated EB by inducing a white adipocyte dysfunction and a decrease in BW, BMR, FI and adipokine secretions without changing the percentage of WAT depots and the morphology of the MOAT.