Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice

Obesity is accompanied by adipocyte death and accumulation of macrophages and mast cells in expanding adipose tissues. Considering the differences in biological behavior of fat found in different anatomical locations, we explored the distribution of mast cells, solitary macrophages, and crown-like structures (CLS), the surrogates for dead adipocytes, in subcutaneous and abdominal visceral fat of lean and diet-induced obese C57BL/6 mice. In fat depots of lean mice, mast cells were far less prevalent than solitary macrophages. Subcutaneous fat contained more mast cells, but fewer solitary macrophages and CLS, than visceral fat. Whereas no significant change in mast cell density of subcutaneous fat was observed, obesity was accompanied by a substantial increase in mast cells in visceral fat. CLS became prevalent in visceral fat of obese mice, and the distribution paralleled mast cells. Adipose tissue mast cells contained and released preformed TNF-α, the cytokine implicated in the pathogenesis of obesity-linked insulin resistance. In summary, subcutaneous fat differed from visceral fat by immune cell composition and a lower prevalence of CLS both in lean and obese mice. The increase in mast cells in visceral fat of obese mice suggests their role in the pathogenesis of obesity and insulin resistance.     

Differential expression of plasminogen activator inhibitor-1, tumor necrosis factor-alpha,TNF-alpha converting enzyme and ADAMTS family members in murine fat territories

Our objective was to investigate expression of A disintegrin and metalloproteinase (ADAM) and ADAM proteins with a thrombospondin (TS) motif (ADAMTS) family members in adipose tissue of lean and obese mice. Five-week-old male mice were kept on standard chow (SFD) or on high fat diet (HFD) for 15 weeks, and subcutaneous (SC) and gonadal (GON) adipose tissue, as well as mature adipocytes and stromal-vascular (S-V) cells were harvested. mRNA levels of plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-alpha (TNF-alpha), ADAM-17 (TACE or TNF-alpha converting enzyme), ADAMTS-1 and ADAMTS-8 were quantified in isolated adipose tissues and cell fractions, and during differentiation of murine preadipocytes. The HFD resulted in a significantly enhanced weight of isolated SC and GON fat pads, and in enhanced blood levels of glucose, cholesterol and PAI-1. ADAM-17, TNF-alpha, PAI-1, ADAMTS-1 and ADAMTS-8 mRNA were detected in both SC and GON adipose tissue of lean mice (SFD). In SC adipose tissue of obese mice (HFD), the expression of ADAM-17 and PAI-1 was enhanced and that of ADAMTS-1 reduced, whereas in GON adipose tissue expression of TNF-alpha was enhanced and that of ADAMTS-8 reduced. In lean and obese mice, expression of ADAM-17, ADAMTS-1 and ADAMTS-8 was higher in the S-V cell fraction than in mature adipocytes. During differentiation of murine 3T3-F442A preadipocytes, expression of ADAM-17 and ADAMTS-1 remained virtually unaltered, whereas that of ADAMTS-8 decreased as adipocytes matured. Several ADAM and ADAMTS family members are expressed in adipose tissue and during differentiation of preadipocytes. Modulation of their expression upon development of obesity is adipose tissue-dependent.     

Comparative studies of the role of hormone-sensitive lipase and adipose triglyceride lipase in human fat cell lipolysis

Hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) regulate adipocyte lipolysis in rodents. The purpose of this study was to compare the roles of these lipases for lipolysis in human adipocytes. Subcutaneous adipose tissue was investigated. HSL and ATGL protein expression were related to lipolysis in isolated mature fat cells. ATGL or HSL were knocked down by RNA interference (RNAi) or selectively inhibited, and effects on lipolysis were studied in differentiated preadipocytes or adipocytes derived from human mesenchymal stem cells (hMSC). Subjects were all women. There were 12 lean controls, 8 lean with polycystic ovary syndrome (PCOS), and 27 otherwise healthy obese subjects. We found that norepinephrine-induced lipolysis was positively correlated with HSL protein levels (P < 0.0001) but not with ATGL protein. Women with PCOS or obesity had significantly decreased norepinephrine-induced lipolysis and HSL protein expression but no change in ATGL protein expression. HSL knock down by RNAi reduced basal and catecholamine-induced lipolysis. Knock down of ATGL decreased basal lipolysis but did not change catecholamine-stimulated lipolysis. Treatment of hMSC with a selective HSL inhibitor during and/or after differentiation in adipocytes reduced basal lipolysis by 50%, but stimulated lipolysis was inhibited completely. In contrast to findings in rodents, ATGL is of less importance than HSL in regulating catecholamine-induced lipolysis and cannot replace HSL when this enzyme is continuously inhibited. However, both lipases regulate basal lipolysis in human adipocytes. ATGL expression, unlike HSL, is not influenced by obesity or PCOS.     

Isolation of two human fibroblastic cell populations with multiple but distinct potential of mesenchymal differentiation by ceiling culture of mature fat cells from subcutaneous adipose tissue

Adipose tissue is a source of adult multipotent stem cells that can differentiate along mesenchymal lineage. When mature fat cells obtained from human subcutaneous adipose tissue were maintained with attachment to the ceiling surface of culture flasks filled with medium, two fibroblastic cell populations appeared at the ceiling and the bottom surface. Both populations were positive to CD13, CD90, and CD105, moderately positive to CD9, CD166, and CD54, negative to CD31. CD34, CD66b, CD106, and CD117, exhibited potential of unlimited proliferation, and differentiated along mesenchymal lineage to produce adipocytes, osteoblasts, and chondrocytes. The population that appeared at the ceiling surface showed higher potential of adipogenic differentiation. These observations showed that the cells tightly attached to mature fat cells can generate two fibroblastic cell populations with multiple but distinct potential of differentiation. Since enough number of both populations for clinical transplantation can be easily obtained by maintaining fat cells from a small amount of subcutaneous adipose tissue, this method has an advantage in preparing autologous cells for patients needing repair of damaged tissues by reconstructive therapy.     

Is genetically transmitted obesity due to an adipose tissue defect?

1. The aim of this investigation was to ascertain of a variety of obese rodents whether the primary cause of fat cell enlargement lay in the fat cell itself, or in its environment. Rodents studied were the mutant mice 'diabetic' (db/db), 'adipose' (dbad/dbad), and 'yellow obese' (Ay/+), New Zealand obese mice, CBA mice made obese with gold thioglucose, and obese BIO 4.24 hamsters. 2. Gonadal fat of obese or lean genotype was transplanted under the kidney capsule of an obese or lean host. Grafts were left in place for at least one month, then examined histologically to measure fat cell diameters, from which fat cell masses were calculated. 3. Immunological rejection of grafts was avoided either by using mice syngeneic except for the obesity producing mutation (db/db, dbad/dbad or Ay/+) or by transplanting into F1 hybrids (NZO X BALB/c) made by mating the strains acting as donors of obese or lean fat. Transplantation of fat between lean BIO 4.22 hamsters and obese BIO 4.24 hamsters was possible because these had common histocompatibility antigens. 4. In all the forms of murine obesity studied, 'lean' fat cells enlarged in an obese recipient to the size typical of cells in 'obese' fat whilst 'obese' fat cells shrunk in a lean recipient to, at least, the size typical of 'lean' fat. Lean hamster fat cells also enlarged in an 'obese' environment and 'obese' hamster cells shrunk in a 'lean' environment. 5. Environment therefore contributes to the determination of fat cell size in all the rodents studied, and in several rodents (db/db, dbad/dbad, Ay/+, and gold thioglucose obese mice) our results showed that environmental factors are of paramount importance in determining cell size, and factors associated with the fat cell itself make a negligible contribution.     

TNF-α mediates the stimulation of sclerostin expression in an estrogen-deficient condition

Obesity consists in fat accumulation leading to increase in adipose cells number and size. Adipocyte membrane biophysical properties are critical to maintain cellular viability in metabolically healthy obesity. This study investigated the effect of the genetic background and dietary protein restriction on fat tissue lipid composition, adipocyte membrane fluidity and water permeability using the pig as experimental model. Twenty-four male pigs from distinct genotypes, lean and obese, were fed on normal and reduced protein diets within a 2 × 2 factorial arrangement (two genotypes and two diets). Backfat thickness was twofold higher in obese than in lean pigs but unrelated to dietary protein level. In contrast, total fatty acids in the subcutaneous adipose tissue were dependent on both breed and diet, with increased lipid content promoted by the fatty genotype and by the restriction of dietary protein. Adipose membranes isolated from obese pig's subcutaneous fat tissue showed higher permeability to water, in line with an increased fluidity. Moreover, the reduced content of dietary protein influenced positively the fluidity of adipose membranes. Neither genotype nor diet affected total cholesterol concentration in the adipose membranes. Membrane-saturated fatty acids' content was influenced by genotype, while membrane-polyunsaturated fatty acids, particularly from the n-6 family, was influenced by diet. The ratio of oleic (18:1c9)/linoleic (18:2n-6) acids was positively correlated with membrane fluidity. All together, these findings reinforce the genetic background as a determinant player on adipose membrane biophysical properties and point to the dietary protein level as an important factor for subcutaneous lipid deposition as well as for regulation of membrane function, factors that may have impact on human obesity and metabolic syndrome.     

The FTO gene is associated with adulthood obesity in the Mexican population

Common polymorphisms in the fat mass and obesity-associated gene (FTO) have shown strong association with obesity in several populations. In the present study, we explored the association of FTO gene polymorphisms with obesity and other biochemical parameters in the Mexican population. We also assessed FTO gene expression levels in adipose tissue of obese and nonobese individuals. The study comprised 788 unrelated Mexican-Mestizo individuals and 31 subcutaneous fat tissue biopsies from lean and obese women. FTO single-nucleotide polymorphisms (SNPs) rs9939609, rs1421085, and rs17817449 were associated with obesity, particularly with class III obesity, under both additive and dominant models (P = 0.0000004 and 0.000008, respectively). These associations remained significant after adjusting for admixture (P = 0.000003 and 0.00009, respectively). Moreover, risk alleles showed a nominal association with lower insulin levels and homeostasis model assessment of B-cell function (HOMA-B), and with higher homeostasis model assessment of insulin sensitivity (HOMA-S) only in nonobese individuals (P (dom) = 0.031, 0.023, and 0.049, respectively). FTO mRNA levels were significantly higher in subcutaneous fat tissue of class III obese individuals than in lean individuals (P = 0.043). Risk alleles were significantly associated with higher FTO expression in the class III obesity group (P = 0.047). In conclusion, FTO is a major risk factor for obesity (particularly class III) in the Mexican-Mestizo population, and is upregulated in subcutaneous fat tissue of obese individuals.     

Differential expression of aquaporin 7 in adipose tissue of lean and obese high fat consumers

Aquaporin 7 (AQP7) is an aquaglyceroprotein responsible for the secretion and uptake of glycerol from the adipocyte. The modulation of the expression of this membrane transport protein might play an important role in the susceptibility to the development of obesity. The aim of the present study was to compare the AQP7 gene expression in subcutaneous abdominal fat in lean vs. obese high fat intakers with a similar daily physical activity pattern. Twelve young men, 6 lean (BMI=23.2+/-0.4kg/m(2)) and 6 obese (35.0+/-1.1kg/m(2)) with a similar habitual dietary intake of fat (45.5+/-2.5 vs. 43.5+/-1.7% daily energy from fat for lean and obese, respectively) and physical activity (16.0+/-5.7 vs. 17.2+/-5.1 METsh/week for lean and obese, respectively), were recruited. Subcutaneous abdominal fat biopsies were obtained and total RNA was extracted and purified. Pools of RNA from lean and obese individuals were probed into Affymetrix GeneChip Human U133A. The microarray analysis revealed that AQP7 gene was down-regulated in obese compared to lean subjects. The results of the microarray analysis were confirmed by real-time PCR studies. In summary, our data show that the AQP7 gene is differentially expressed in adipose tissue of lean and obese individuals. The down-regulation of the AQP7 gene could be implicated in the susceptibility to obesity by reducing glycerol release and promoting the accumulation of lipids in the adipose tissue.     

Serum leptin, lipids, free fatty acids, and fat pads in long-term dehydroepiandrosterone-treated Zucker rats

The obese Zucker rat has a genetically flawed leptin system and is a model of hyperphagia, obesity, hyperlipidemia, and markedly elevated leptin levels. Dehydroepiandrosterone (DHEA) administration reduces hyperphagia, hyperlipidemia, and obesity in Zucker rats. Since serum leptin levels are associated with body fat, we wondered what the effects of fat pad weight reduction from DHEA administration would have on leptin levels. This experiment investigated the effects of DHEA on intra-abdominal fat pads, serum lipids, and peripheral leptin in male lean and obese Zucker rats that were administered DHEA in their food from 4 weeks of age to 20 weeks. Lean and obese rats received plain chow or chow containing DHEA. Additional chow-fed groups of lean and obese weight-matched controls and obese pair-fed rats helped to control for the reduced body weight, food intake, and fat pad weights seen with DHEA administration. DHEA administration to lean Zucker rats reduced body weight and fat pad weights, but leptin levels showed a lower trend. Among obese rats, both DHEA treatment and pair-feeding reduced body weight and fat pad weights, but only DHEA lowered leptin levels. The weight-matched controls had reductions in fat pad weights similar to the DHEA-treated group, but with increased leptin levels. Thus, DHEA may exert a small, independent effect on leptin levels in this animal model, but the reduction is less than what would be expected.     

Visceral fat accumulation induced by a high-fat diet causes the atrophy of mesenteric lymph nodes in obese mice

Objective: A high intake of fat in the diet plays a crucial role in promoting obesity and obesity‐related pathologies, and especially visceral obesity is closely associated with obesity‐related complications. Because adipose tissue is anatomically associated with lymph nodes, the secondary lymphoid organ, we hypothesized that fat tissue‐derived factors may influence the cellularity of lymphoid tissue embedded in fat. Methods and Procedures: Mesenteric and inguinal lymph nodes were isolated from obese mice fed a high‐fat diet and control mice fed a regular diet. T‐cell population, activation state, and the extent of apoptosis were determined by flow cytometric analysis or terminal deoxynucleotidyl transferase biotin‐dUTP nick end labeling (TUNEL) assay. Results: The weight of mesenteric lymph nodes and the total number of lymphoid cells in the obese mice significantly decreased compared with those in the control mice; however, no change was observed in the weight of inguinal lymph nodes. The numbers of CD4⁺ and CD8⁺ T cells in the mesenteric lymph nodes of obese mice significantly decreased compared with those of the control. Enhanced T‐cell activation and apoptosis were observed in the mesenteric lymph node cells of the obese mice. The treatment of lymph node cells with free fatty acids, oxidative stress, and chylomicrons, which are obesity‐related factors, resulted in lymph node T‐cell activation and apoptosis. Discussion: These results suggest that visceral fat accumulation with a high‐fat diet can cause the atrophy of mesenteric lymph nodes by enhancing activation‐induced lymphoid cell apoptosis. Dietary fat‐induced visceral obesity may be crucial for obesity‐related immune dysfunction.     

Uptake of thyroxine by cultured human adipocyte precursors isolated from lean and obese subjects.

The mechanism of thyroxine uptake by human adipocyte precursors has been studied in primary culture. Also the rates of transport of this hormone into the isolated cells of adipose tissue were compared for lean and obese subjects. It was demonstrated that thyroxine transport into the human adipocyte precursor cells is an active, energy-dependent process characterized by very low rate (Km = 10 pmol/l, Vmax = 8 fmol FT4/10(6) cells/min.). By comparing the rates of thyroxine transport into the precursor cells of adipocytes isolated from adipose tissue of lean and obese subjects it was possible to demonstrate a clear tendency to the lowered rate of transport of thyroxine to the cells in obesity. The results of this study suggest that the lowered rate of thyroxine transport to preadipocytes and adipocytes observed in obesity may significantly influence the metabolic state of these cells.     

Lipogenesis from glucose and pyruvate in fat cells from genetically obese rats

Subcutaneous fat cells were isolated from genetically obese rats and from rats with obesity produced by hypothalamic lesions. Insulin did not augment the oxidation of fatty acids or their synthesis from glucose-1-(14)C or glucose-1-(3)H by fat cells from either group. Radioactivity from pyruvate-3-(14)C was incorporated into fatty acids to the same degree by fat cells from these two groups. The presence of 5 mm glucose in the incubation medium containing fat cells and pyruvate-3-(14)C or aspartate-3-(14)C stimulated the synthesis of fatty acids to a greater extent in cells of genetically obese rats. Fasting, in contrast, reduced the incorporation of radioactivity from pyruvate and glucose into fatty acids by fat cells from the genetically obese animals. In all experiments the fat cells from genetically obese rats converted more radioactivity into glyceride-glycerol relative to CO(2) than did fat cells from hypothalamic obese rats. Parabiosis between one thin and one genetically obese litter mate was performed in three pairs of rats without influencing growth of either rat. Thus in the present studies fat cells from genetically obese rats showed two differences from normal fat cells: they channeled more radioactivity from pyruvate into fatty acids in the presence of glucose, and they uniformly converted more radioactivity into glyceride-glycerol.     

Effects of obesity on the relationship of leptin mRNA expression and adipocyte size in anatomically distinct fat depots in mice

In support of leptin's physiological role as humoral signal of fat mass, we have shown that adipocyte volume is a predominant determinant of leptin mRNA levels in anatomically distinct fat depots in lean young mice in the postabsorptive state. In this report, we investigated how obesity may affect the relationship between leptin mRNA levels and adipocyte volume in anatomically distinct fat depots in mice with genetic (Lep(ob)/Lep(ob) and A(y)/+), diet-induced, and aging-related obesity. In all of the obese mice examined, tissue leptin mRNA levels relative to the average adipocyte volume were lower in the perigonadal and/or retroperitoneal than in the inguinal fat depots and were lower than those of the lean young mice in the perigonadal fat depot. A close, positive correlation between leptin mRNA level and adipocyte volume was present from small to hypertrophic adipocytes within each perigonadal and inguinal fat pad in the obese mice, but the slopes of the regression lines relating leptin mRNA level to adipocyte volume were significantly lower in the perigonadal than in the inguinal fat pads of the same mice. These results suggest that obesity per se is associated with a decreased leptin gene expression per unit of fat mass in mice and that the positive correlation between leptin mRNA level and adipocyte volume is an intrinsic property of adipocytes that is not disrupted by adipocyte hypertrophy in obese mice.     

Abnormal fatty acid utilization by cultured cardiac cells from 7-day-old obese Zucker rats

Fatty acid utilization by muscle and nonmuscle heart cells in culture has been investigated in the 7-day-old Zucker rat to determine if this tissue could contribute to the lower energy expenditure reported in obese rats at the onset of obesity. The partitioning of oleate to oxidation and esterification products and the effect of genotype on this partitioning according to cell types were studied. Results showed that the fatty acid beta-oxidation and its esterification in neutral lipid was decreased by 30% in beating muscle cells from obese animals when compared with those from lean animals. In contrast, nonmuscle cells exhibited a decreased beta-oxidation alone. A similar fatty acid composition of the phospholipids was found in non-muscle cells of obese animals and their lean litter mates. In muscle cultures, palmitic and oleic acids are lower in cells of obese rats than in those of lean rats. The present study indicates that a defect in energy metabolism could be found in heart cells at the onset of obesity, suggesting that this defect is determined by intrinisic factor(s).     

The lipid-mobilizing effect of atrial natriuretic peptide is unrelated to sympathetic nervous system activation or obesity in young men

We recently demonstrated that natriuretic peptides and especially the atrial natriuretic peptide (ANP) are powerful lipolytic agents on isolated human fat cells. To search for a possible influence of obesity on ANP responsiveness, we compared the lipolytic effects of human ANP (h-ANP) on isolated subcutaneous abdominal adipose tissue (SCAAT) fat cells from young healthy lean and obese men. The lipid-mobilizing effects of an intravenous infusion of h-ANP was studied, as well as various metabolic and cardiovascular parameters that were compared in the same subjects. h-ANP (50 ng/min/kg) was infused iv for 60 min. Microdialysis probes were inserted in SCAAT to measure modifications of the extracellular glycerol concentrations during h-ANP infusion. Spectral analysis of blood pressure and heart rate oscillations that were recorded using digital photoplethysmography were used to assess changes in autonomic nervous system activity. h-ANP induced a marked and similar increase in glycerol and nonesterified fatty acids, and a weak increase in insulin plasma levels in lean and obese men. Plasma norepinephrine concentrations rose similarly during h-ANP infusion in lean and obese men. The effects of h-ANP infusion on the autonomic nervous system were similar in both groups, with an increase in the spectral energy of the low-frequency band of systolic blood pressure variability and a decrease in the spectral energy of the high-frequency band of heart rate. In SCAAT, h-ANP infusion increased extracellular glycerol concentration and decreased blood flow similarly in both groups. The increase in extracellular glycerol observed during h-ANP infusion was not modified when 0.1 mM propranolol was added to the microdialysis probe perfusate to prevent beta-adrenoceptor activation. These data show that ANP is a potent lipolytic hormone independent of the activation of the sympathetic nervous system, and that obesity did not modify the lipid-mobilizing effect of ANP in young obese subjects.     

Inflammation Correlates With Markers of T‐Cell Subsets Including Regulatory T Cells in Adipose Tissue From Obese Patients

Accumulation of cytotoxic and T‐helper (T_h)1 cells together with a loss of regulatory T cells in gonadal adipose tissue was recently shown to contribute to obesity‐induced adipose tissue inflammation and insulin resistance in mice. Human data on T‐cell populations in obese adipose tissue and their potential functional relevance are very limited. We aimed to investigate abundance and proportion of T‐lymphocyte sub‐populations in human adipose tissue in obesity and potential correlations with anthropometric data, insulin resistance, and systemic and adipose tissue inflammation. Therefore, we analyzed expression of marker genes specific for pan‐T cells and T‐cell subsets in visceral and subcutaneous adipose tissue from highly obese patients (BMI >40 kg/m², n = 20) and lean to overweight control subjects matched for age and sex (BMI <30 kg/m²; n = 20). All T‐cell markers were significantly upregulated in obese adipose tissue and correlated with adipose tissue inflammation. Proportions of cytotoxic T cells and T_h1 cells were unchanged, whereas those of regulatory T cells and T_h2 were increased in visceral adipose tissue from obese compared to control subjects. Systemic and adipose tissue inflammation positively correlated with the visceral adipose abundance of cytotoxic T cells and T_h1 cells but also regulatory T cells within the obese group. Therefore, this study confirms a potential role of T cells in human obesity‐driven inflammation but does not support a loss of protective regulatory T cells to contribute to adipose tissue inflammation in obese patients as suggested by recent animal studies.     

Insulin stimulation of particulate, low Km adenosine 3',5'-monophosphate phosphodiesterase activity in fat cells of the obese-hyperglycemic (ob/ob) mouse.

Cyclic AMP phosphodiesterase activity was examined in particulate (30,000 X g for 30 min sediment) and supernatant subcellular fractions of epididymal fat cells isolated from obese-hyperglycemic (ob/ob) mice and their lean (+/?) LITTERMATES. The activity of the enzyme(s) was measured during both the early onset phase (5-6 weeks of age) and the static (5 months of age) of the obese-hyperglycemia syndrome. Fat cell particulate and supernate cyclic AMP phosphodiesterase activity of obese-hyperglycemic mice and their lean littermates at both ages displayed nonlinear Lineweaver-Burk kinetic plots. The maximum velocities of the fat cell particulate cyclic AMP phosphodiesterase activity of the obese mice were 67% and 84% lower than those of their lean littermates at 5-6 weeks and 5 months of age, respectively. Incubating fat cells obtained from either lean or obese mice of both age groups with 30 to 240 microunits of insulin per ml for 15 min increased the activity of the particulate, low Km cyclic AMP phosphodiesterase. This increase in activity was manifest as an increase in the maximum velocity of the enzyme(s) with no significant alteration of the affinity of the enzyme(s) for cyclic AMP.     

No Impairment in Host Defense against Streptococcus pneumoniae in Obese CPEfat/fat Mice

In the US and globally, dramatic increases in the prevalence of adult and childhood obesity have been reported during the last 30 years. In addition to cardiovascular disease, type II diabetes, and liver disease, obesity has recently been recognized as an important risk factor for influenza pneumonia. During the influenza pandemic of 2009, obese individuals experienced a greater severity of illness from the H1N1 virus. In addition, obese mice have also been shown to exhibit increased lethality and aberrant pulmonary inflammatory responses following influenza infection. In contrast to influenza, the impact of obesity on bacterial pneumonia in human patients is controversial. In this report, we compared the responses of lean WT and obese CPE^fat/fat mice following an intratracheal infection with Streptococcus pneumoniae, the leading cause of community-acquired pneumonia. At 16 weeks of age, CPE^fat/fat mice develop severe obesity, hyperglycemia, elevated serum triglycerides and leptin, and increased blood neutrophil counts. There were no differences between lean WT and obese CPE^fat/fat mice in survival or lung and spleen bacterial burdens following intratracheal infection with S. pneumoniae. Besides a modest increase in TNF-α levels and increased peripheral blood neutrophil counts in CPE^fat/fat mice, there were not differences in lung or serum cytokines after infection. These results suggest that obesity, accompanied by hyperglycemia and modestly elevated triglycerides, at least in the case of CPE^fat/fat mice, does not impair innate immunity against pneumococcal pneumonia.