David A. Brockman

Lipocalin-2 deficiency impairs thermogenesis and potentiates diet-induced insulin resistance in mice.

OBJECTIVE Lipocalin (LCN) 2 belongs to the lipocalin subfamily of low–molecular mass–secreted proteins that bind small hydrophobic molecules. LCN2 has been recently characterized as an adipose-derived cytokine, and its expression is upregulated in adipose tissue in genetically obese rodents. The objective of this study was to investigate the role of LCN2 in diet-induced insulin resistance and metabolic homeostasis in vivo. RESEARCH DESIGN AND METHODS Systemic insulin sensitivity, adaptive thermogenesis, and serum metabolic and lipid profile were assessed in LCN2-deficient mice fed a high-fat diet (HFD) or regular chow diet. RESULTS The molecular disruption of LCN2 in mice resulted in significantly potentiated diet-induced obesity, dyslipidemia, fatty liver disease, and insulin resistance. LCN2−/− mice exhibit impaired adaptive thermogenesis and cold intolerance. Gene expression patterns in white and brown adipose tissue, liver, and muscle indicate that LCN2−/− mice have increased hepatic gluconeogenesis, decreased mitochondrial oxidative capacity, impaired lipid metabolism, and increased inflammatory state under the HFD condition. CONCLUSIONS LCN2 has a novel role in adaptive thermoregulation and diet-induced insulin resistance.

High-Viscosity Dietary Fibers Reduce Adiposity and Decrease Hepatic Steatosis in Rats Fed a High-Fat Diet

Viscous dietary fiber consumption lowers the postprandial glucose curve and may decrease obesity and associated comorbidities such as insulin resistance and fatty liver. We determined the effect of 2 viscous fibers, one fermentable and one not, on the development of adiposity, fatty liver, and metabolic flexibility in a model of diet-induced obesity. Rats were fed a normal-fat (NF) diet (26% energy from fat), a high-fat diet (60% energy from fat), each containing 5% fiber as cellulose (CL; nonviscous and nonfermentable), or 5% of 1 of 2 highly viscous fibers-hydroxypropyl methylcellulose (HPMC; nonfermentable) or guar gum (GG; fermentable). After 10 wk, fat mass percentage in the NF (18.0%; P = 0.03) and GG groups (17.0%; P < 0.01) was lower than the CL group (20.7%). The epididymal fat pad weight of the NF (3.9 g; P = 0.04), HPMC (3.9 g; P = 0.03), and GG groups (3.6 g; P < 0.01) was also lower than the CL group (5.0 g). The HPMC (0.11 g/g liver) and GG (0.092 g/g liver) groups had lower liver lipid concentrations compared with the CL group (0.14 g/g liver). Fat mass percentage, epididymal fat pad weight, and liver lipid concentration were not different among the NF, HPMC, and GG groups. The respiratory quotient was higher during the transition from the diet-deprived to fed state in the GG group (P = 0.002) and tended to be higher in the HPMC group (P = 0.06) compared with the CL group, suggesting a quicker shift from fatty acid (FA) to carbohydrate oxidation. The HPMC group [15.1 nmol/(mg ⋅ h)] had higher ex vivo palmitate oxidation in muscle compared with the GG [11.7 nmol/(mg ⋅ h); P = 0.04] and CL groups [10.8 nmol/(mg ⋅ h); P < 0.01], implying a higher capacity to oxidize FAs. Viscous fibers can reduce the adiposity and hepatic steatosis that accompany a high-fat diet, and increase metabolic flexibility, regardless of fermentability.

Lipocalin 2 Deficiency Alters Estradiol Production and Estrogen Receptor Signaling in Female Mice

We have previously characterized lipocalin 2 (Lcn2) as a new adipokine having a critical role in energy and lipid metabolism in male mice. Previous studies by others have suggested that Lcn2 is a putative target gene of estrogens. In this study, we reported the effect of Lcn2 deficiency on estradiol biosynthesis and estrogen receptor signaling in female Lcn2-deficient (Lcn2-/-) mice. We found that Lcn2 expression in white adipose tissue is gender, depot, and age dependent. In female mice, Lcn2 is predominantly expressed in inguinal adipose tissue but at relatively very low levels in perigonadal depot and ovary. After 22 wk of high-fat diet (HFD) feeding or at old age, Lcn2-/- female mice had significantly reduced levels of serum 17β-estradiol and down-regulated expression of estrogen receptor α in multiple metabolic tissues. Consistently, the expression of estrogen-regulated genes involved in cholesterol homeostasis, such as liver X receptor β and low-density lipoprotein receptor was also down-regulated in the adipose tissue of Lcn2-/- mice. These changes were in line with the development of atherogenic dyslipidemia in response to HFD feeding; female Lcn2-/- mice had significantly elevated levels of total cholesterol and low-density lipoprotein cholesterol, whereas reduced high-density lipoprotein cholesterol levels compared with wild-type female mice. Interestingly, when compared with wild-type controls, HFD-fed female Lcn2-/- mice had significantly reduced expression levels of aromatase, a key enzyme regulating estradiol biosynthesis, in adipose tissue. Moreover, Lcn2 deficiency markedly blunted age-related increase in adipose aromatase expression but had no significant impact on age-related reduction in ovarian aromatase expression. Our findings suggest that Lcn2 has a tissue-specific role in adipose estradiol biosynthesis, which may link Lcn2 to obesity- and age-related estradiol production and metabolic complications in females.

Hydroxypropyl methylcellulose, a viscous soluble fiber, reduces insulin resistance and decreases fatty liver in Zucker Diabetic Fatty rats

BackgroundDiets producing a high glycemic response result in exaggerated insulin secretion which induces hepatic lipogenesis, contributing to development of insulin resistance and fatty liver. Viscous dietary fibers blunt the postprandial rise in blood glucose, however their effect on type 2 diabetes and obesity are not entirely known. This study examined the effect of chronic consumption of the viscous, non-fermentable dietary fiber, hydroxypropyl methylcellulose (HPMC), on glucose control, insulin resistance and liver lipids in an obese diabetic rat model.MethodsThree groups of Zucker Diabetic Fatty (ZDF) rats were fed diets containing either 5% non-viscous cellulose (control), low viscosity HPMC (LV-HPMC) or high viscosity HPMC (HV- HPMC) for six weeks. Zucker lean littermates consuming cellulose served as a negative control. Markers of glucose control, including oral glucose tolerance test, glycated hemoglobin and urinary glucose, were measured as well as adiposity and the accumulation of liver lipids.ResultsThe HPMC diets increased the viscosity of the small intestinal contents and reduced the postprandial rise in blood glucose. The food efficiency ratio was greater with HPMC feeding compared to the obese control and urinary excretion of glucose and ketone bodies was reduced. The two HPMC groups had lower glycated hemoglobin and kidney weights and a reduced area under the curve during a glucose tolerance test, indicating improved glucose control. Epididymal fat pad weight as percent of body weight was reduced in the HV-HPMC group compared to the obese control group. The HV-HPMC group also had lower concentrations of liver lipid and cholesterol and reduced liver weight. However, HV-HPMC feeding did not affect hepatic gene expression of SREBP-1c or FAS. Muscle concentration of acylcarnitines, a lipid intermediate in fatty acid β-oxidation, was not different between the HPMC groups and obese control, suggesting no change in muscle fatty acid oxidation by HPMC.ConclusionsConsumption of the viscous non-fermentable fiber HPMC decreased diabetic wasting, improved glucose control and reduced insulin resistance and fatty liver in a model of obesity with diabetes.

Proteomics in the characterization of adipose dysfunction in obesity.

Adipose tissue plays a central role in body weight homeostasis, inflammation, and insulin resistance via serving as a fat-buffering system, regulating lipid storage and mobilization and releasing a large range of adipokines and cytokines. Adipose tissue is also the major inflammation-initiated site in obesity. Adipose-derived adipokines and cytokines are known to be involved in the modulation of a wide range of important physiological processes, particularly immune response, glucose and lipid homeostasis and insulin resistance. Adipose tissue dysfunction, characterized by an imbalanced secretion of pro- and anti-inflammatory adipokines and cytokines, decreased insulin-stimulated glucose uptake, dysregulation of lipid storage and release and mitochondrial dysfunction, has been linked to obesity and its associated metabolic disorders. Proteomic technology has been a powerful tool for identifying key components of the adipose proteome, which may contribute to the pathogenesis of adipose tissue dysfunction in obesity. In this review, we summarized the recent advances in the proteomic characterization of adipose tissue and discussed the identified proteins that potentially play important roles in insulin resistance and lipid homeostasis.