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Effect of omega-3 fatty acids on serum concentrations of adipokines in healthy cats

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  • 1 Department of Pathobiology and Diagnostic Investigation, Diagnostic Center for Population and Animal Health, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
  • | 2 Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
  • | 3 Department of Pathobiology and Diagnostic Investigation, Diagnostic Center for Population and Animal Health, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

Abstract

Objective—To determine associations between serum concentrations of omega-3 polyunsaturated fatty acids and concentrations of adiponectin, leptin, and insulin in healthy cats.

Animals—56 healthy adult client-owned cats.

Procedures—Body condition score (BCS) was determined, and blood samples were collected after food was withheld for 12 hours. Serum was harvested for fatty acid analysis and measurement of serum concentrations of adiponectin, leptin, insulin, glucose, triglyceride, and cholesterol.

Results—1 cat was removed because of hyperglycemia. Significant interaction effects between BCS and serum concentrations of eicosapentaenoic acid (EPA) were detected for the analyses of associations between EPA and serum concentrations of adiponectin, insulin, and triglyceride. Cats were categorized into nonobese (BCS, 4 to 6 [n = 34 cats]) and obese (BCS, 7 to 8 [21]) groups; serum concentrations of EPA were directly associated with concentrations of adiponectin and inversely associated with concentrations of insulin and triglyceride in obese cats and were directly associated with concentrations of leptin and inversely associated with concentrations of adiponectin in nonobese cats. Additionally, serum concentrations of docosahexaenoic acid were directly associated with concentrations of adiponectin in obese cats. No significant associations between serum concentrations of docosahexaenoic acid or α-linolenic acid were detected in the analyses for all cats. Female cats had higher serum concentrations of adiponectin and lower concentrations of glucose than did male cats. Increased age was associated with a small increase in serum concentrations of leptin.

Conclusions and Clinical Relevance—EPA may ameliorate the decrease in adiponectin and the increase in insulin and triglyceride concentrations in obese cats.

Adipose tissue plays an important role in energy homeostasis by serving as a storage organ and also through active secretion of adipokines, including adiponectin and leptin. Body fat content in cats is inversely associated with circulating concentrations of adiponectin and directly associated with concentrations of leptin, which is similar to findings in humans and other animals.1–4 Adiponectin, the most abundant adipokine, exerts a profound insulin-sensitizing effect by enhancing FA oxidation in skeletal muscle and the liver, thus reducing triglyceride content in these tissues. It also facilitates glucose uptake by skeletal muscle and inhibits glucose production by the liver, which leads to a decrease in blood glucose concentrations.5 Adiponectin also has anti-inflammatory and antiatherosclerotic effects.6,7 Leptin is an important regulator of adipose tissue mass and increases insulin sensitivity through multiple effects on satiety, energy expenditure, and neuroendocrine function. These effects are exerted predominantly through actions of leptin within the CNS and possibly by additional direct effects on insulin target tissues.8

Because adiponectin concentrations are decreased in obese subjects, low adiponectin concentrations are implicated in the pathogenesis of several metabolic alterations associated with obesity in humans, including insulin resistance and type 2 diabetes mellitus.7 Increased leptin concentrations also have been reported in association with insulin resistance and most likely indicate leptin resistance.8 Similarly in cats, low adiponectin and high leptin concentrations have been associated with obesity-related insulin resistance.4,9 In a preliminary report,a investigators indicated that diabetic status as well as body condition are predictors of low adiponectin concentrations in cats.

Authors of numerous studies10–22 have described beneficial effects of consumption of diets high in n-3 PUFAs on various disorders; many of those disorders are also associated with low concentrations of adiponectin. In an epidemiological study10 in humans, dietary intake of fish products, which are rich in long-chain n-3 PUFAs (EPA and DHA), was associated with a delay in the development of glucose intolerance. Obese cats consuming a diet high in n-3 PUFAs had improvement in long-term glucose control and decreases in plasma insulin concentrations, compared with results for cats consuming a diet rich in saturated FAs.22

Dietary FAs have also been associated with circulating concentrations of adiponectin and leptin. In healthy humans, serum adiponectin concentrations are directly associated with concentrations of n-3 PUFAs and inversely associated with n-6 PUFAs and saturated FAs.23 Increased leptin concentrations are associated with decreased n-3 PUFA concentrations in humans with acute myocardial infarction.17

Low adiponectin concentrations and high leptin concentrations in cats with insulin resistance and the reported improvement in insulin sensitivity as a result of dietary n-3 PUFAs suggest that the beneficial effects of these FAs may be mediated through an increase in adiponectin concentrations. Therefore, we hypothesized that circulating n-3 PUFA concentrations are directly associated with adiponectin concentrations in cats. The objective of the study reported here was to determine the associations between serum concentrations of n-3 PUFAs and concentrations of adiponectin, leptin, and insulin in healthy cats.

Materials and Methods

Animals—Fifty-six healthy adult (≥ 1 year old) client-owned cats admitted to the Veterinary Teaching Hospital at Michigan State University for routine examinations were included in the study. Cats were considered healthy on the basis of results of physical examination and routine biochemical analysis. Additional inclusion criteria reflected the medical and dietary history for a 3-month period preceding sample collection and included absence of any clinical signs indicative of illness, exclusive feeding of a commercially available nutritionally balanced and complete diet formulated for adult cats (based on Association of American Feed Control Officials minimums), and no administration of dietary nutritional products or medications. Cats with mild hyperglycemia (up to 9.0 mmol/L) were not excluded. This magnitude of increase in glucose concentration was considered to represent stress hyperglycemia consistent with a reported mean peak glucose concentration of 9.0 mmol/L in healthy cats that were subjected to an acute stressor but that had results for a glucose tolerance test within the anticipated reference limits.24 Informed consent was obtained from all owners. The study was performed in compliance with Michigan State University guidelines for research in animals.

Sample collection and serum analysis—Food was withheld from all cats for 12 hours before sample collection. Before sample collection, body condition of all cats was evaluated by a single investigator (PAS) and scored by use of a BCS system (scale, 1 to 9).25 A venous blood sample (2 mL) was collected from each cat. The sample was centrifuged (2,000 × g for 15 minutes at 4°C) immediately after clotting; serum was harvested and frozen at −20°C until analyzed.

Serum adiponectin, leptin, and insulin concentrations were measured by use of commercially available assaysb–d previously used by others2,4 and validated in our laboratory for use in cats. Serum samples were diluted 1:1,111 in preparation for the adiponectin assay. For validation, serial dilutions of cat serum were prepared, and the observed curves were parallel to the standard curves for mouse adiponectin, human leptin, and human insulin standards. The dynamic range and minimum detection limit of the assays were 0.25 to 8 ng/mL and 15.6 pg/mL in diluted serum for adiponectin, 1 to 50 ng/mL and 1 ng/mL for leptin, and 36 to 2,153 pmol/L and 9 pmol/L for insulin, respectively. Intra-assay and interassay coefficients of variation were 5% and 7% for adiponectin, 6% and 10% for leptin, and 9% and 10% for insulin, respectively. Serum glucose concentrations were measured by use of an automated chemistry analyzer,e and concentrations of cholesterol and triglyceride were measured by use of a spectrophotometric method.f

Analysis of serum FA concentrations was performed by use of gas chromatography. Fatty acids in serum samples were methylated by incubation with 10% methanolic HCl at 75°C for 2 hours.26 Nonadecanoic acid was used as an internal standard. Samples (1 μL) of FA methyl esters in hexane were injected into the gas chromatograph.g A fused silica capillary column (100 m × 0.25 mm with a film thickness of 0.2 μm)h was used to resolve the FA methyl esters in each sample. Hydrogen was used as a carrier gas at a flow rate of 0.5 mL/min. The resolved components were detected by a flame ionization detector with an air flow of 400 mL/min and a hydrogen flow of 45 mL/min; the temperature of the detector was set at 255°C. Peaks were identified and validated by use of FA standards of known concentrations.i Serum FA concentrations were reported as percentages of total FAs.

Data analysis—Associations between serum concentrations of EPA, DHA, and ALA and serum concentrations of adiponectin, leptin, insulin, glucose, triglyceride, and cholesterol were evaluated by use of a general linear model that included EPA concentration, DHA concentration, ALA concentration, BCS, sex, and age as covariates. Lack of potential colinearity among serum concentrations of EPA, DHA, and ALA was confirmed. The additional covariates (ie, BCS, sex, and age) were included to control for potential confounding of the association between EPA, DHA, or ALA concentration and the outcome variables (adiponectin, leptin, insulin, glucose, triglyceride, or cholesterol concentration). The link function and the linear predictor for each of the variables were of the form E(y|x) = a + bx, where y is a natural logarithmic transformation of the measured values and has a normal distribution (as confirmed by examination of probability-probability plots) with a mean (a + bx) and constant variances. All interaction effects between EPA, DHA, or ALA concentrations and other variables in the models were assessed.

Post hoc categorization—Significant interaction effects between BCS and EPA concentration were detected in the analyses of the associations with adiponectin (P = 0.023), insulin (P = 0.025), and triglyceride (P = 0.006) concentrations. An interaction effect, which was not significant (P = 0.060), between BCS and DHA concentration was detected in the analysis of the associations with adiponectin concentration. Because of insufficient statistical power of the study to evaluate the effect of EPA concentration on the outcome variables in separate analyses of each BCS category with age and sex as additional covariates, cats were categorized into 2 groups (nonobese [BCS, 4 to 6] and obese [BCS, 7 to 8]) on the basis of the likelihood for a positive or negative association between EPA and adiponectin concentrations in the following separate analyses: exponentiated coefficients for the association between EPA and adiponectin concentrations in the analyses for BCS of 4, 5, 6, 7, and 8 were 0.11 (P > 0.10), 0.42 (P < 0.10), 0.87 (P > 0.10), 5.39 (P < 0.10), and 1.91 (P > 0.10), respectively. Associations between serum concentrations of EPA and DHA and serum concentrations of adiponectin, leptin, insulin, glucose, triglyceride, or cholesterol were evaluated separately for the non-obese and obese groups by use of a general linear model that included EPA concentration, DHA concentration, and sex as covariates in all models. Age was entered as an additional covariate in the models for all the outcome variables, except adiponectin concentration because its inclusion in the model decreased the model's adjusted R2. The ALA concentration was not included in the separate models because its inclusion decreased the model's adjusted R2.

Results were reported for all cats when no interaction effects were detected (associations of sex, age, DHA concentration, and ALA concentration with all outcome variables and associations of EPA concentration with leptin, glucose, and cholesterol concentrations) and separately for the nonobese and obese groups when significant interaction effects were detected (associations of EPA concentration with adiponectin, insulin, and triglyceride concentrations) as well as further evaluation of the associations between EPA concentration and leptin, glucose, and cholesterol concentrations or DHA concentration with all outcome variables. Data were analyzed by use of a commercially available statistical program.j A value of P < 0.05 was considered significant.

Results

One neutered female cat was excluded from the study because of hyperglycemia (serum glucose concentration, 14.8 mmol/L) in the serum sample obtained after food was withheld for 12 hours. The BCS of the remaining 55 cats was 4 (n = 5 cats), 5 (15), 6 (14), 7 (9), and 8 (12). Thus, 34 cats were categorized as nonobese and 21 were categorized as obese.

Median age of the nonobese cats was 3.0 years (interquartile range, 1.5 to 6.5 years), whereas that of the obese cats was 5.0 years (interquartile range, 3.5 to 7.0 years). Fourteen nonobese cats were neutered males and 20 were neutered females. Sixteen obese cats were neutered males and 5 were neutered females. The nonobese group comprised 26 domestic shorthair cats, 3 domestic longhair cats, 2 mixed-breed cats, 1 Siamese, 1 Birman, and 1 Bengal. The obese group comprised 14 domestic shorthair cats, 4 domestic longhair cats, 2 domestic medium-hair cats, and 1 mixed-breed cat. Median (interquartile range) serum concentrations of ALA, EPA, and DHA were 0.21 mg/100 mg of FAs (0 to 0.35 mg/100 mg of FAs), 0.34 mg/100 mg of FAs (0 to 0.48 mg/100 mg of FAs), and 1.75 mg/100 mg of FAs (1.37 to 2.82 mg/100 mg of FAs), respectively, in the nonobese group and 0.36 mg/100 mg of FAs (0.28 to 0.56 mg/100 mg of FAs), 0.21 mg/100 mg of FAs (0.06 to 0.44 mg/100 mg of FAs), and 2.15 mg/100 mg of FAs (1.29 to 2.66 mg/100 mg of FAs), respectively, in the obese group.

Serum glucose concentration was higher than the reference range of 3.3 to 7.5 mmol/L in 5 nonobese and 2 obese cats. Serum triglyceride concentration was higher than the reference range of 21 to 155 mg/dL in 5 cats in the obese group and was within the reference range in all cats in the nonobese group. Serum concentration of cholesterol was within the reference range of 77 to 306 mg/dL in all cats.

Analysis of data for all cats revealed that the adjusted geometric mean serum concentration of adiponectin was 71% higher and the adjusted geometric mean serum glucose concentration was 15% lower in neutered females than in neutered males (Table 1). In addition, each 1-year increase in age was associated with a 2% increase in the adjusted geometric mean serum concentration of leptin (Table 2).

Table 1—

Effect of sex on adiponectin, leptin, insulin, glucose, triglyceride, and cholesterol concentrations in 55 healthy neutered cats.*

VariableRatio (95% CI)P valuePartial η2
Adiponectin1.71 (1.10–2.66)0.0190.12
Leptin1.11 (0.95–1.29)0.1870.04
Insulin0.95 (0.74–1.22)0.689< 0.01
Glucose0.85 (0.76–0.95)0.0060.16
Triglyceride0.91 (0.71–1.16)0.4450.01
Cholesterol1.02 (0.86–1.20)0.865< 0.01

Values reported are the ratio (95% CI) of adjusted geometric means of serum concentrations for female cats to serum concentrations for male cats for each variable.

Covariates in the general linear model include age, sex, BCS, and concentrations of EPA, DHA, and ALA.

Table 2—

Effect of age on adiponectin, leptin, insulin, glucose, triglyceride, and cholesterol concentrations in 55 healthy cats.*

VariableFold increase (95% CI)P valuePartial η2
Adiponectin0.98 (0.93–1.04)0.4920.01
Leptin1.02 (1.00–1.04)0.0480.08
Insulin0.97 (0.94–1.00)0.0570.08
Glucose0.99 (0.98–1.00)0.2240.04
Triglyceride0.98 (0.95–1.01)0.2240.03
Cholesterol1.01 (0.99–1.03)0.2570.03

Values represent the fold increase (95% CI) in adjusted geometric means of serum concentrations of each variable for each 1-year increase of age.

See Table 1 for remainder of key.

A significant association between serum concentrations of EPA and leptin was detected in the analysis for all cats; an increase in the serum concentration of EPA of 1 mg/100 mg of FAs was associated with a 314% increase in the adjusted geometric mean serum concentration of leptin (95% CI fold increase of adjusted geometric mean, 1.07 to 15.21; P = 0.039; partial η2 = 0.09). No significant associations between EPA concentration and glucose or cholesterol concentrations or between DHA or ALA concentrations and any of the outcome variables were detected in the analyses for all cats.

In the separate analyses for the nonobese group, an increase in the serum concentration of EPA of 1 mg/100 mg of FAs was associated with a 62% decrease in the adjusted geometric mean serum concentration of adiponectin and a 43% increase in the adjusted geometric mean serum concentration of leptin (Table 3). In the separate analyses for the obese group, an increase in the serum concentration of EPA of 1 mg/100 mg of FAs was associated with a 643% increase in the adjusted geometric mean serum concentration of adiponectin, a 70% decrease in the adjusted geometric mean serum concentration of insulin, and an 84% decrease in the adjusted geometric mean serum concentration of triglyceride (Table 4). Additionally, an increase in the serum concentration of DHA of 1 mg/100 mg of FAs was associated with a 54% increase in the adjusted geometric mean serum concentration of adiponectin in the separate analysis for the obese group (95% CI fold increase of adjusted geometric mean, 1.02 to 2.32; P = 0.041; partial η2 = 0.22). No significant associations were detected between serum concentrations of DHA and adiponectin in the separate analysis for the nonobese group or between serum concentration of DHA and concentrations of leptin, insulin, glucose, triglyceride, or glucose in the separate analyses for the nonobese or obese groups.

Table 3—

Effect of EPA on adiponectin, leptin, insulin, glucose, triglyceride, and cholesterol concentrations in 34 nonobese (BCS, 4 to 6) cats.*

VariableMean (95% CI)Fold increase (95% CI)P valuePartial η2
Adiponectin (μg/mL)2.4 (1.8–3.1)0.38 (0.17–0.83)0.0170.18
Leptin (ng/mL)4.4 (4.1–4.8)1.43 (1.12–1.83)0.0060.23
Insulin (pmol/L)34 (29–39)0.95 (0.61–1.50)0.833< 0.01
Glucose (mmol/L)5.7 (5.3–6.1)0.97 (0.78–1.20)0.772< 0.01
Triglyceride (mg/dL)65 (58–72)0.84 (0.61–1.16)0.2760.04
Cholesterol (mg/dL)128 (117–140)0.87 (0.67–1.13)0.2920.04

Covariates in the general linear model include sex, age, EPA, and DHA concentration (leptin, insulin, glucose, triglyceride, and cholesterol concentrations) or sex, EPA, and DHA concentration (adiponectin concentration).

Covariates in the models are evaluated at their mean values as follows: EPA = 0.31 mg/100 mg of FAs, DHA = 1.98 mg/100 mg of FAs, and age = 4.9 years.

Fold increases (95% CI) of adjusted geometric means of serum concentration of each variable represent the change with an increase in serum concentration of EPA of 1 mg/100 mg of FAs.

Table 4—

Effect of EPA concentration on adiponectin, leptin, insulin, glucose, triglyceride, and cholesterol concentrations in 21 obese (BCS, 7 or 8) cats.*

VariableMean (95% CI)Fold increase (95% CI)P valuePartial η2
Adiponectin (μg/mL)1.3 (0.8–2.0)7.43 (1.05–52.30)0.0450.22
Leptin (ng/mL)5.8 (4.8–7.1)0.84 (0.35–2.01)0.6740.01
Insulin (pmol/L)46 (36–60)0.30 (0.10–0.91)0.0350.25
Glucose (mmol/L)5.1 (4.6–5.7)0.98 (0.93–1.02)0.3030.07
Triglyceride (mg/dL)97 (71–134)0.16 (0.04–0.65)0.0140.32
Cholesterol (mg/dL)137 (116–161)0.96 (0.47–1.97)0.908< 0.01

Covariates in the models are evaluated at their mean values as follows: EPA = 0.24 mg/100 mg of FAs, DHA = 1.92 mg/100 mg of FAs, and age = 4.9 years.

See Table 3 for remainder of key.

Discussion

In the study reported here, it was found that circulating concentrations of adipokines (adiponectin and leptin), insulin, and triglyceride are associated with serum concentrations of long-chain n-3 PUFAs but not with concentrations of n-3 PUFAs of shorter chain lengths (ie, ALA) in healthy cats. These associations were detected primarily for EPA and differed between nonobese and obese cats. Specifically, concentrations of EPA were directly associated with concentrations of adiponectin and inversely associated with concentrations of insulin and triglyceride in obese cats. A direct association of serum concentrations of EPA with concentrations of leptin and an inverse association with concentrations of adiponectin were detected in the nonobese cats. The only significant finding for serum concentrations of DHA was a direct association with concentrations of adiponectin in obese cats, which was similar to the finding for EPA concentrations.

Although a cause-and-effect relationship cannot be determined from this cross-sectional study, a potential regulatory effect of long-chain n-3 PUFAs on adiponectin production and secretion in obese cats is suggested by the finding of direct associations of serum concentrations of adiponectin with concentrations of both EPA and DHA. The concentration of each of these FAs explained 22% of the variability in adiponectin concentration in the obese cats. These findings are in agreement with the reported direct association between circulating plasma adiponectin and n-3 PUFA concentrations in humans.23 In addition, other investigators27–32 have detected an increase in adiponectin concentration following dietary supplementation with n-3 PUFAs in rodents and humans, which supports a causal effect of these FAs on adiponectin secretion.

Long-chain n-3 PUFAs may have an effect that attenuates processes that occur in adipose tissue as it expands and result in reduced adiponectin production and secretion. One potential effect of these FAs is attenuation of the inflammation in adipose tissue of obese subjects.33 Tumor necrosis factor-α protein and mRNA concentrations were found to be higher in adipose tissue of obese cats,34,35 compared with results for lean cats, and increased TNF-α concentrations have been associated with downregulation of adiponectin production in cocultured adipocytes and macrophages.36 It has been suggested that in contrast to saturated FAs, n-3 PUFAs are unable to activate macrophages and may antagonize the proinflammatory effect of saturated FAs; the reduction of inflammation in adipose tissue then restores adiponectin production.30,37,38 A fish oil-enriched diet was associated with significant reductions in inflammatory cytokines and lymphocyte proliferation in dogs,12,13 but no significant differences in general immune function were found between cats fed diets rich in omega-3 PUFAs or saturated FAs.39 However, cytokine concentrations were not evaluated in that study in cats.39

Another potential mechanism by which n-3 PUFAs restore adiponectin concentrations in obese subjects is upregulation and activation of PPAR-γ. This nuclear receptor plays a key role in lipid and glucose homeostasis through effects on gene transcription, and its pharmacological activation can increase adiponectin concentrations.40 The PPAR-γ is expressed predominantly in adipose tissue, and its expression is decreased in obese cats.41 Eicosapentaenoic acid increases PPAR-γ expression in adipocytes,42 and DHA metabolites may act as ligands for PPAR-γ.28,43 It is possible that EPA and DHA decreased the inflammatory process and reversed the downregulation of PPAR-γ in the obese cats of the study reported here, which restored adiponectin concentrations.

An inverse association between EPA and adiponectin concentrations was found in the nonobese group, and the concentration of EPA explained 18% of the variability in adiponectin concentration in the nonobese cats. A potential explanation for this finding is not clearly apparent. Some clarification may be provided by the reported dose-dependent effect of EPA on PPAR-γ expression in isolated human adipocytes, which was characterized by an initial increase and a subsequent decrease of PPAR-γ expression at high EPA concentrations.42 Higher EPA concentrations could lead to suppression of the already high baseline PPAR-γ expression in relatively lean cats, which would result in lower circulating adiponectin concentrations.

A direct association of leptin concentration and EPA concentration was detected when data for all cats were analyzed, and further analysis of the subgroups revealed that this association was evident in nonobese cats but not in obese cats. This difference may have been related to the smaller number of obese cats than nonobese cats in the study. Alternatively, EPA may upregulate leptin production in nonobese cats but not in obese cats because of the high leptin concentrations resulting from leptin resistance in obese cats. The concentration of EPA explained 23% of the variability in leptin concentration in the nonobese cats in the present study. In other studies, there have been conflicting results regarding the effect of n-3 PUFAs on leptin concentrations. Some studies have indicated an increase,29,44,45 some have indicated a decrease,46,47 and others have indicated no change11,21 in leptin concentrations or mRNA expression following dietary supplementation with fish oil. The reason for these variable findings is unclear but could be related to study design or species differences.

An inverse association between serum concentrations of insulin and EPA was found in the obese cats but not in the nonobese cats. Concentration of EPA explained 25% of the variability in insulin concentration in the obese cats. These findings suggest a potential regulatory effect of EPA on insulin sensitivity and, consequently, insulin concentrations in obese cats. These findings agree with the reported beneficial effects of fish oil consumption on insulin sensitivity in humans and the decreased insulin concentrations in obese cats following feeding of a diet rich in n-3 PUFAs, compared with results after feeding a diet high in saturated FAs.22

The effect of n-3 PUFAs on insulin sensitivity may be mediated by increased adiponectin production and secretion because adiponectin has profound insulin-sensitizing properties. However, n-3 PUFAs may have additional insulin-sensitizing effects that are not directly related to increased adiponectin concentrations. Upregulation and activation of PPAR-γ by n-3 PUFAs in adipose tissue lead to transformation of small adipocytes that are more sensitive to insulin. Increased incorporation of n-3 PUFAs in cell membranes of insulin target tissues results in improved insulin activity. Omega-3 PUFAs may stimulate FA oxidation in the liver and skeletal muscle, which decreases tissue lipid accumulation and improves insulin action and may also improve glucose utilization by attenuation of obesity-induced downregulation of glucose transporter-4 in insulin target tissues.15,20,45 The effect of n-3 PUFAs to improve insulin sensitivity may also be mediated through reduction of adipose tissue TNF-α concentrations because TNF-α impairs insulin signaling by inhibiting tyrosine kinase activity of insulin receptors.48

Serum triglyceride concentrations were inversely associated with EPA concentrations in obese cats but not in nonobese cats. Concentration of EPA explained 32% of the variability in triglyceride concentration in the obese cats. Results of other studies support the lipid-lowering effect of EPA and fish oil in humans15,16 and dogs.49,50 The hypolipidemic effect of n-3 PUFAs is attributable to the suppression of transcription of genes encoding lipogenic enzymes and to increased FA oxidation in the liver.51 Additional beneficial effects on hyperlipidemia include stimulation of lipoprotein lipase activity, decrease in intestinal absorption of lipid and glucose, increase in cholesterol secretion into bile, and decrease in cholesterol absorption.14,18,19 The effect of n-3 PUFAs to decrease triglyceride concentrations may be partially mediated through suppression of TNF-α because TNF-α stimulates secretion of very–low-density lipoproteins from the liver and increases lipolysis in adipose tissue.52 Although studies22,53 in healthy cats have revealed no effect of dietary supplementation with n-3 PUFAs on triglyceride concentration, the findings of the study reported here warrant further investigation into the effect of EPA on triglyceride concentrations in hyperlipidemic cats.

In the present study, associations were detected between concentrations of adipokines, insulin, and triglyceride with concentrations of long-chain n-3 PUFAs (primarily EPA) but not with n-3 PUFAs of shorter chain length (ie, ALA). If the potential biological effect of n-3 PUFAs is exerted via the long-chain n-3 PUFAs, then the lack of effect of the shorter-length n-3 PUFAs may be explained by the greatly limited conversion of ALA to the longer-chain derivatives (ie, EPA and DHA) because of low Δ-6 desaturase activity in cats.54

Sex accounted for 12% of the variability in serum concentrations of adiponectin. Higher concentrations were found in female cats than in male cats, which is similar to the sex effect on adiponectin concentrations reported in humans.55,56 A direct effect of testosterone to decrease adiponectin secretion has been proposed as the primary factor for this sex difference in humans and rodents,55 but it cannot explain the finding in the population of neutered cats in the present study. A study56 in a group of male and female human subjects of similar age and body condition revealed an inverse association of concentrations of adiponectin and nonesterified FAs in men but not in women, which suggests that additional factors may be involved in the effect of sex on adiponectin concentrations. Further evaluation of potential sex differences (other than those attributable to sex hormones) that may affect adiponectin production in neutered cats is warranted. The small increase in leptin concentration with age in the cats in the present study is of questionable clinical importance. Age-related increases in leptin concentrations in rodents is thought to result from decreased leptin signaling in the hypothalamus and development of leptin resistance.57

For the study reported here, we concluded that circulating concentrations of EPA in obese cats are directly associated with adiponectin concentrations and inversely associated with insulin and triglycerides concentrations. These findings suggest beneficial effects of EPA in obese cats, and further investigation into the regulatory effect of fish oil and individual n-3 PUFAs on adiponectin and leptin secretion, insulin sensitivity, and lipid metabolism is warranted to determine the potential role of n-3 PUFAs in the prevention and treatment of disorders associated with obesity in cats.

ABBREVIATIONS

ALA

α-Linolenic acid

BCS

Body condition score

CI

Confidence interval

DHA

Docosahexaenoic acid

EPA

Eicosapentaenoic acid

FA

Fatty acid

PPAR

Peroxisome proliferator-activated receptor

PUFA

Polyunsaturated fatty acid

TNF

Tumor necrosis factor

a.

Brömel C, Nelson RW, Fascetti AJ, et al. Determination of adiponectin, a novel adipocyte hormone, in healthy and diabetic normal weight and obese cats (abstr). J Vet Intern Med 2004;18:403.

b.

Mouse/rat adiponectin ELISA kit, B-Bridge, Mountain View, Calif.

c.

Multispecies leptin RIA kit, Millipore, St Charles, Mo.

d.

Human insulin RIA kit, Diagnostic Systems Laboratories, Webster, Tex.

e.

AU640 chemistry-immuno analyzer, Olympus America, Center Valley, Pa.

f.

Kodak Ektachem DT60 II, Eastman Kodak Co, Rochester, NY.

g.

Clarus 500 gas chromatograph, Perkin Elmer, Shelton, Conn.

h.

SP2560 fused-silica capillary column, Supelco, Bellefonte, Pa.

i.

Nu-check Prep, Elysian, Minn.

j.

SPSS, version 15.0 for Windows, SPSS Inc, Chicago, Ill.

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Contributor Notes

Supported by the American Academy of Veterinary Nutrition-Waltham Research Grant.

Address correspondence to Dr. Mazaki-Tovi (mazaki-tovi@dcpah.msu.edu).