Effect of omega-3 polyunsaturated fatty acids and body condition on serum concentrations of adipokines in healthy dogs

Michal Mazaki-Tovi Department of Pathobiology and Diagnostic Investigation, Diagnostic Center for Population and Animal Health, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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Sarah K. Abood Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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Patricia A. Schenck Department of Pathobiology and Diagnostic Investigation, Diagnostic Center for Population and Animal Health, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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Abstract

Objective—To determine associations between serum concentrations of omega-3 polyunsaturated fatty acids or body condition and serum concentrations of adiponectin, leptin, insulin, glucose, or triglyceride in healthy dogs.

Animals—62 healthy adult client-owned dogs.

Procedures—Body condition score and percentage of body fat were determined. Blood samples were collected after food was withheld for 12 hours. Serum was harvested for total lipid determination, fatty acid analysis, and measurement of serum concentrations of adiponectin, leptin, insulin, glucose, and triglyceride. Associations between the outcome variables (adiponectin, leptin, insulin, glucose, and triglyceride concentrations) and each of several variables (age, sex, percentage of body fat, and concentrations of total lipid, α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) were determined.

Results—Serum concentrations of docosapentaenoic acid were significantly positively associated with concentrations of adiponectin and leptin and negatively associated with concentrations of triglyceride. Serum concentrations of α-linolenic acid were significantly positively associated with concentrations of triglyceride. No significant associations were detected between serum concentrations of eicosapentaenoic acid or docosahexaenoic acid and any of the outcome variables. Percentage of body fat was significantly positively associated with concentrations of leptin, insulin, and triglyceride but was not significantly associated with adiponectin concentration. Age was positively associated with concentrations of leptin, insulin, and triglyceride and negatively associated with concentrations of adiponectin. Sex did not significantly affect serum concentrations for any of the outcome variables.

Conclusions and Clinical Relevance—Docosapentaenoic acid may increase serum concentrations of adiponectin and leptin and decrease serum triglyceride concentration in healthy dogs.

Abstract

Objective—To determine associations between serum concentrations of omega-3 polyunsaturated fatty acids or body condition and serum concentrations of adiponectin, leptin, insulin, glucose, or triglyceride in healthy dogs.

Animals—62 healthy adult client-owned dogs.

Procedures—Body condition score and percentage of body fat were determined. Blood samples were collected after food was withheld for 12 hours. Serum was harvested for total lipid determination, fatty acid analysis, and measurement of serum concentrations of adiponectin, leptin, insulin, glucose, and triglyceride. Associations between the outcome variables (adiponectin, leptin, insulin, glucose, and triglyceride concentrations) and each of several variables (age, sex, percentage of body fat, and concentrations of total lipid, α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) were determined.

Results—Serum concentrations of docosapentaenoic acid were significantly positively associated with concentrations of adiponectin and leptin and negatively associated with concentrations of triglyceride. Serum concentrations of α-linolenic acid were significantly positively associated with concentrations of triglyceride. No significant associations were detected between serum concentrations of eicosapentaenoic acid or docosahexaenoic acid and any of the outcome variables. Percentage of body fat was significantly positively associated with concentrations of leptin, insulin, and triglyceride but was not significantly associated with adiponectin concentration. Age was positively associated with concentrations of leptin, insulin, and triglyceride and negatively associated with concentrations of adiponectin. Sex did not significantly affect serum concentrations for any of the outcome variables.

Conclusions and Clinical Relevance—Docosapentaenoic acid may increase serum concentrations of adiponectin and leptin and decrease serum triglyceride concentration in healthy dogs.

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 is considered the major determinant of circulating concentrations of adiponectin and leptin in humans and other species.1,2 Similarly, most studies3–9 in dogs have found body condition to be inversely related to circulating concentrations of adiponectin and directly related to concentrations of leptin. Nevertheless, the association between body condition and adiponectin in dogs appears to be weaker, compared with the association between body condition and leptin,3 and some studies10–13 have failed to reveal any relationship between adiponectin and body condition. These conflicting findings suggest that factors other than body fat content may have an important effect on determining circulating adiponectin concentrations in dogs.

Adiponectin exerts profound insulin-sensitizing and lipid-lowering effects through its actions on the skeletal muscle and liver in humans and laboratory rodents.14 It also has anti-inflammatory and antiatherosclerotic effects.15,16 Therefore, low adiponectin concentrations are implicated in the pathogenesis of several metabolic alterations that are associated with obesity in humans, including insulin resistance, dyslipidemia, and atherosclerosis.16 Leptin is an important regulator of energy homeostasis, neuroendocrine function, and metabolism. It increases insulin sensitivity predominantly through actions within the CNS and possibly by additional direct effects at insulin target tissues.17,18 An increased leptin concentration in obesity indicates the presence of leptin resistance.17 Decreased concentrations of adiponectin and increased concentrations of leptin have also been detected in dogs with experimentally induced obesity that had insulin resistance.19 In a recent study11 in dogs with naturally occurring obesity, insulin sensitivity was negatively associated with serum leptin concentrations but no association was detected between insulin sensitivity and adiponectin concentrations.

In numerous studies, beneficial effects of n-3 PUFAs have been described for various disorders in humans and other animals. Cardioprotective, hypolipidemic, and anti-inflammatory effects of n-3 PUFAs have been reported in dogs,20–25 similar to findings in humans.26–28 In addition, a delay in the development of glucose intolerance was associated with consumption of diets high in n-3 PUFAs in humans.29 Many of these disorders are associated with low concentrations of adiponectin,16 but findings regarding leptin are less consistent.

The weak association between circulating concentrations of adiponectin and body condition in dogs suggests the presence of additional important factors for determining adiponectin concentrations. Dietary supplementation with n-3 PUFAs is beneficial for various disorders that are associated with low adiponectin concentrations, so these FAs may serve as a potential means for increasing adiponectin concentrations. Therefore, we hypothesized that circulating n-3 PUFA concentrations are directly related to adiponectin concentrations in dogs, independent of body condition. The objectives of the study reported here were to determine the associations between body condition or serum concentrations of n-3 PUFAs and serum concentrations of adiponectin, leptin, insulin, glucose, or triglyceride in healthy dogs and to assess variation in the relationship between n-3 PUFAs and these outcome variables with body condition.

Materials and Methods

Animals—Sixty-two healthy adult (≥ 1 year old) client-owned dogs admitted to the Veterinary Teaching Hospital at Michigan State University for routine examination were included in the study. Lean, overweight, and obese dogs were enrolled, regardless of body condition. Dogs were considered healthy on the basis of results of physical examination and routine biochemical analysis. Additional inclusion criteria were determined on the basis of the medical and dietary history for a 3-month period preceding sample collection; these criteria included the absence of any clinical signs indicating illness; exclusive feeding of any brand of commercially available, nutritionally balanced, and complete diet formulated for adult dogs; and no administration of dietary supplement-type products or medications other than routine anthelmintics. The study was performed in compliance with Michigan State University guidelines for research in animals. Informed consent was obtained from all owners.

Body condition evaluation and sample collection—Prior to sample collection, body condition of all dogs was evaluated by 1 individual (PAS) using a BCS system (scale of 1 to 9).30 In addition, estimated percentage of body fat was calculated on the basis of morphological measurements, including pelvic circumference and distance from the tarsal joint to the stifle joint as follows31,a:
article image

where BF is percentage of body fat, PC is pelvic circumference, and TS is the tarsal joint-to-stifle joint distance. Food was withheld from each dog for 12 hours. A venous blood sample (2 mL) was then collected. Immediately after clotting, the sample was centrifuged (2,000 × g for 15 minutes at 4°C); serum was harvested and frozen at −20°C until analyzed.

Serum analysis—Serum concentrations of adiponectin, leptin, and insulin were measured by use of commercially available assaysb–d previously used for canine samples7–9; assays were used in accordance with the manufacturers' instructions. Serum samples were diluted 1:2,000 for analysis via the adiponectin assay. The dynamic ranges of the assays were 0.14 to 100 ng/mL in diluted serum for adiponectin, 0.78 to 50 ng/mL for leptin, and 9 to 2,153 pmol/L for insulin. Intra-assay and interassay coefficients of variation were 4% and 8% for adiponectin, 4% and 8% for leptin, and 9% and 10% for insulin. Serum concentrations of triglyceride and glucose were measured via a spectrophotometric method.e

Serum FA analysis was performed with gas chromatography. Lipid was extracted from 400 μL of each serum sample by use of a mixture of hexane and ethanol (1:1 [vol/vol]). Total lipid concentration was determined, and 2.2 mg of lipid was resuspended in 0.5 mL of hexane that contained heptadecanoic acid (2 mg/mL) as an internal standard. Fatty acids were methylated with 10% methanolic HCl at 75°C for 1 hour.32 Samples (1 μL) of FA methyl esters were injected into the gas chromatograph.f A fused silica capillary column (100 × 0.25 mm with a 0.2-μm film thickness)g 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 via a flame ionization detector with an airflow of 400 mL/min and a hydrogen flow rate of 45 mL/min; the temperature of the detector was set at 255°C. Peaks were identified and validated with FA standards of known concentrations.h Serum FA concentrations were reported as the percentage of total FAs.

Data analysis—Basal insulin sensitivity was estimated with fasting concentrations of insulin and glucose by calculation of homeostasis model assessment (insulin resistance) with a nonlinear equation (HOMA2-IR).33,34,i

Associations between individual n-3 PUFAs and each of the outcome variables (serum concentrations of adiponectin, leptin, insulin, triglyceride, or glucose or value of HOMA2-IR) were evaluated via general linear models that included concentrations of ALA (C18:3-n3), EPA (C20:5-n3), DPA (C22:5-n3), and DHA (C22:6-n3); concentration of total lipid (except the model for triglyceride); percentage of body fat; and age as covariates and sex as a fixed factor in a single model. Absence of potential multicolinearity among the covariates was confirmed. The additional covariates and factor (concentration of total lipid, percentage of body fat, age, and sex) were included to control for potential confounding of the relationship between the FA and the outcome variables. All interaction effects between FA and the additional covariates in the models were assessed. The link function and the linear predictor for the outcome variables in each of the models were determined in accordance with the following equation: E(Y/x) = a + bx, where Y is a natural logarithmic transformation of the measured values of the outcome variables and has a normal distribution (as confirmed by P-P plots) with a mean (ie, a + bx) and constant variances of the residual across the range of fitted values. All hypotheses of the present study were defined a priori, and the relationships between the exposure and outcome variables were each of specific interest; therefore, adjustment for multiple comparisons as a result of testing > 1 hypothesis was not applied. The effect of each exposure variable across its observed range on the outcome variable was reported as range of effect and was calculated by multiplying the covariate's coefficient and the ratio of the 10th to 90th percentile ranges of the covariate and the outcome variable.35 Data were analyzed with a commercially available statistical program.j Values of P < 0.05 were considered significant.

Results

Animals—The study population consisted of 18 neutered males, 32 spayed females, 4 sexually intact males, and 8 sexually intact females. Dogs were of various breeds, and 12 were mixed-breed dogs. The prevalent breeds included Labrador Retriever (n = 10), Golden Retriever (6), English Cocker Spaniel (5), Australian Shepherd Dog (5), Brittany (3), German Shepherd Dog (3), American Cocker Spaniel (2), Border Collie (2), Rottweiler (2), and Saluki (2).

Median and range of the covariates and outcome variables were summarized (Table 1). The BCS ranged from 4 to 9 (median, 5.5). The distribution of BCS and percentage of body fat was plotted (Figure 1).

Table 1—

Median and range values for age, percentage of body fat, and serum concentrations of individual n-3 PUFAs, total lipid, adiponectin, leptin, insulin, triglyceride, and glucose in 62 healthy dogs.

VariableMedianRange
Age (y)5.81–13
Body fat (%)252–58
ALA (mg/100 mg of FAs)00–1.88
EPA (mg/100 mg of FAs)0.150–4.74
DPA (mg/100 mg of FAs)1.250–2.69
DHA (mg/100 mg of FAs)0.800–6.24
Total lipid (mg/mL)9.55.5–17.0
Adiponectin (μg/mL)7.52.1–34.0
Leptin (ng/mL)6.70.4–35.9
Insulin (pmol/L)11335–469
Triglyceride (mg/dL)6222–214
Glucose (mg/dL)8964–113
Figure 1—
Figure 1—

Distribution for the percentage of body fat among BCS categories in 62 healthy dogs. Each symbol represents results for 1 dog.

Citation: American Journal of Veterinary Research 73, 8; 10.2460/ajvr.73.8.1273

Concentrations of triglyceride were higher than the reference range of 21 to 116 mg/dL in 10 dogs. Concentrations of glucose were higher than the reference range of 70 to 100 mg/dL in 10 dogs and less than the reference range in 1 dog.

Model fitting—Sex was not significantly associated with serum concentrations of adiponectin, leptin, insulin, triglyceride, or glucose or insulin resistance; therefore, sex was removed from all models. All other covariates were retained in all models. No significant interactions were detected between FA and the additional covariates in the models; therefore, all interaction terms were removed from all models.

Effects of n-3 PUFAs—Serum concentrations of DPA were significantly positively associated with serum concentrations of adiponectin and leptin and negatively associated with serum concentrations of triglyceride (Table 2). There was no significant association between serum concentrations of DPA and serum concentrations of insulin or glucose; there also was no significant (P = 0.4) association between serum concentrations of DPA and insulin resistance. Associations between the measured serum concentrations of DPA and serum concentrations of adiponectin, leptin, triglyceride, or insulin were plotted (Figure 2). These associations, adjusted for age, percentage of body fat, and serum concentrations of ALA, EPA, DHA, and total lipid (except triglyceride), were also plotted (Figure 3).

Table 2—

Effect of DPA on serum concentrations of adiponectin, leptin, insulin, triglyceride, and glucose in 62 healthy dogs.*

VariableFold increase (95% CI)Range of effect (95% CI)P value§
Adiponectin1.68 (1.27–2.22)0.46 (0.22 to 0.71)< 0.001
Leptin1.51 (1.04–2.21)0.19 (0.02 to 0.36)0.032
Insulin0.99 (0.76–1.29)−0.01 (−0.24 to 0.23)1.0
Triglyceride0.83 (0.70–0.98)−0.21 (−0.40 to-0.02)0.032
Glucose0.98 (0.90–1.07)−0.09 (−0.51 to 0.34)0.7

Covariates in the general linear model include age, percentage of body fat, and serum concentrations of ALA, EPA, DPA, DHA, and total lipid (except the model for triglyceride).

Represents the fold increase in adjusted geometric means of the serum concentration of each variable as a result of an increase in the serum concentration of DPA of 1 mg/100 mg of FAs.

Range of effect was calculated by multiplying the coefficient of DPA by the ratio of the 10th to 90th percentile range of DPA concentration to the 10th to 90th percentile range of each outcome variable concentration.

Values were considered significant at P < 0.05.

Figure 2—
Figure 2—

Association between serum concentrations of adiponectin (A), leptin (B), triglyceride (C), and insulin (D) and serum concentrations of DPA in 62 healthy dogs. Scatterplots represent the measured serum concentrations of outcome variables on a natural logarithmic scale versus the measured serum concentrations of DPA. Each symbol represents results for 1 dog.

Citation: American Journal of Veterinary Research 73, 8; 10.2460/ajvr.73.8.1273

Figure 3—
Figure 3—

Partial association between serum concentrations of adiponectin (A), leptin (B), triglyceride (C), or insulin (D) and serum concentrations of DPA adjusted for potential confounders in 62 healthy dogs. Scatterplots represent the residuals from the models of the outcome variables (natural logarithmically transformed) versus the residual from the model of serum concentrations of DPA. Covariates in each of the models of the outcome variables and serum concentrations of DPA include age, percentage of body fat, and serum concentrations of ALA, EPA, DHA, and total lipid (except for the model for triglyceride). Each symbol represents results for 1 dog.

Citation: American Journal of Veterinary Research 73, 8; 10.2460/ajvr.73.8.1273

Serum concentrations of ALA were significantly positively associated with serum concentrations of triglyceride. There were no significant associations between serum concentrations of ALA and serum concentrations of adiponectin, leptin, insulin, or glucose (Table 3) or insulin resistance (P = 0.4). No significant associations were detected between serum concentrations of EPA or DHA and serum concentrations of adiponectin, leptin, insulin, triglyceride or glucose (Tables 4 and 5). In addition, there were no significant associations between serum concentrations of EPA or DHA and insulin resistance (P = 0.7 and P = 0.8, respectively).

Table 3—

Effect of ALA on serum concentrations of adiponectin, leptin, insulin, triglyceride, and glucose in 62 healthy dogs.*

VariableFold increase (95% CI)Range of effect (95% CI)P value§
Adiponectin0.81 (0.50–1.31)−0.05 (−0.17 to 0.06)0.4
Leptin0.82 (0.42–1.60)−0.02 (−0.11 to 0.06)0.5
Insulin0.89 (0.57–1.41)−0.03 (−0.14 to 0.08)0.6
Triglyceride1.53 (1.12–2.09)0.13 (0.03 to 0.22)0.009
Glucose0.99 (0.85–1.15)−0.01 (−0.21 to 0.18)0.9

Represents the fold increase in adjusted geometric means of the serum concentration of each variable as a result of an increase in the serum concentration of ALA of 1 mg/100 mg of FAs.

Range of effect was calculated by multiplying the coefficient of ALA by the ratio of the 10th to 90th percentile range of ALA concentration to the 10th to 90th percentile range of each outcome variable concentration.

See Table 2 for remainder of key.

Table 4—

Effect of EPA on serum concentrations of adiponectin, leptin, insulin, triglyceride, and glucose in 62 healthy dogs.*

VariableFold increase (95% CI)Range of effect (95% CI)P value§
Adiponectin0.95 (0.67–1.36)−0.02 (−0.18 to 0.14)0.8
Leptin0.66 (0.40–1.08)−0.10 (−0.21 to 0.02)0.1
Insulin1.05 (0.75–1.47)0.02 (−0.13 to 0.17)0.8
Triglyceride1.02 (0.80–1.29)0.01 (−0.12 to 0.14)0.9
Glucose1.01 (0.90–1.13)0.02 (−0.26 to 0.31)0.9

Represents the fold increase in adjusted geometric means of the serum concentration of each variable as a result of an increase in the serum concentration of EPA of 1 mg/100 mg of FAs.

Range of effect was calculated by multiplying the coefficient of EPA by the ratio of the 10th to 90th percentile range of EPA concentration to the 10th to 90th percentile range of each outcome variable concentration.

See Table 2 for remainder of key.

Table 5—

Effect of DHA on serum concentrations of adiponectin, leptin, insulin, triglyceride, and glucose in 62 healthy dogs.*

VariableFold increase (95% CI)Range of effect (95% CI)P value§
Adiponectin1.00 (0.78–1.27)−0.004 (−0.22 to 0.22)1.0
Leptin1.07 (0.75–1.52)0.03 (−0.13 to 0.19)0.7
Insulin0.97 (0.77–1.22)−0.03 (−0.24 to 0.18)0.8
Triglyceride0.95 (0.81–1.12)−0.05 (−0.23 to 0.13)0.3
Glucose1.00 (0.93–1.08)0.01 (−0.37 to 0.39)1.0

Represents the fold increase in adjusted geometric means of the serum concentration of each variable as a result of an increase in the serum concentration of DHA of 1 mg/100 mg of FAs.

Range of effect was calculated by multiplying the coefficient of DHA by the ratio of the 10th to 90th percentile range of DHA concentration to the 10th to 90th percentile range of each outcome variable concentration.

See Table 2 for remainder of key.

Effects of body condition and age—Percentage of body fat was significantly positively associated with serum concentrations of leptin, insulin, or triglyceride (Table 6). Percentage of body fat also was significantly (P < 0.001) positively associated with insulin resistance (fold increase, 1.03 [95% CI, 1.02 to 1.04]; range of effect, 0.59 [95% CI, 0.33 to 0.85]). No significant association was detected between the percentage of body fat and serum concentrations of adiponectin or glucose.

Table 6—

Effect of percentage of body fat on serum concentrations of adiponectin, leptin, insulin, triglyceride, and glucose in 62 healthy dogs.*

VariableFold increase (95% CI)Range of effect (95% CI)P value§
Adiponectin0.99 (0.98–1.01)−0.10 (−0.36 to 0.16)0.4
Leptin1.07 (1.05–1.08)0.69 (0.51 to 0.88)< 0.001
Insulin1.02 (1.01–1.04)0.49 (0.24 to 0.74)< 0.001
Triglyceride1.02 (1.01–1.03)0.51 (0.30 to 0.71)< 0.001
Glucose1.00 (1.00–1.01)0.38 (−0.07 to 0.82)0.093

Represents the fold increase in adjusted geometric means of the serum concentration of each variable as a result of an increase in body fat of 1%.

Range of effect was calculated by multiplying the coefficient of percentage of body fat by the ratio of the 10th to 90th percentile range of percentage of body fat to the 10th to 90th percentile range of each outcome variable concentration.

See Table 2 for remainder of key.

Age was significantly associated with serum concentrations of adiponectin, leptin, and insulin (Table 7). No significant association was detected between age and serum concentrations of triglyceride or glucose. In addition, there was no significant (P = 0.4) association between age and insulin resistance.

Table 7—

Effect of age on serum concentrations of adiponectin, leptin, insulin, triglyceride, and glucose in 62 healthy dogs.*

VariableFold increase (95% CI)Range of effect (95% CI)P value§
Adiponectin0.92 (0.88–0.96)−0.37 (−0.58 to-0.17)0.001
Leptin1.08 (1.01–1.16)0.19 (0.03 to 0.34)0.018
Insulin1.04 (1.00–1.09)0.2 (0.005 to 0.40)0.045
Triglyceride1.02 (0.99–1.06)0.13 (−0.04 to 0.31)0.1
Glucose0.99 (0.97–1.00)−0.33 (−0.70 to 0.04)0.083

Represents the fold increase in adjusted geometric means of the serum concentration of each variable as a result of an increase in age of 1 year.

Range of effect was calculated by multiplying the coefficient of age by the ratio of the 10th to 90th percentile range of age to the 10th to 90th percentile range of each outcome variables concentration.

See Table 2 for remainder of key.

Discussion

In the study reported here, associations were detected between serum concentrations of n-3 PUFAs and serum concentrations of adiponectin, leptin, and triglyceride in healthy dogs. Although a cause-and-effect relationship cannot be established by this cross-sectional study, these findings support a potential regulatory effect of n-3 PUFAs on the production of adipokines and lipid metabolism. Docosapentaenoic acid was the only n-3 PUFA associated with serum concentrations of adiponectin and leptin, which suggested that this FA may have an important effect among the n-3 PUFAs; alternatively, it may serve as an indicator for a general effect of n-3 PUFAs. Both DPA and ALA concentrations were associated with serum triglyceride concentrations. However, these associations were opposite (DPA concentrations were negatively associated, and ALA concentrations were positively associated); thus the potential effect of n-3 PUFAs on triglyceride metabolism is unclear.

The direct relationship between serum concentrations of DPA and adiponectin suggested a regulatory effect of this FA on adiponectin production and secretion in dogs. Concentration of DPA accounted for 46% of the range of adiponectin concentrations. These findings are in general agreement with findings in cats36 as well as the reported direct relationship between circulating plasma adiponectin and n-3 PUFA concentrations in human subjects.37–39 Additional studies40–45 have revealed an increase in adiponectin concentration following dietary supplementation with long-chain n-3 PUFAs in rodents as well as in human subjects, which supports a causal effect of these FAs on adiponectin secretion.

Potential effects of long-chain n-3 PUFAs to increase concentrations of adiponectin may be mediated through their attenuating effects on various processes that occur during obesity and lead to decreased production and secretion of adiponectin. Obesity is associated with inflammation in adipose tissue in humans,46 and increased concentrations of TNF-α have also been reported in obese dogs.12,47 Tumor necrosis factor-α decreases adiponectin mRNA expression and secretion in cultured human48 and canine49 adipose tissue. It has been suggested that n-3 PUFAs, in contrast to saturated FAs, are unable to activate macrophages and may antagonize the proinflammatory effect of saturated FAs.50,51 Specifically, derivatives of DHA and DPA can inhibit the production of proinflammatory cytokines.52 In dogs, dietary supplementation with fish oil was associated with significant reductions in activities of inflammatory cytokines and lymphocyte proliferation,53,54 which exemplifies the anti-inflammatory effect of n-3 PUFAs in dogs. Obesity in dogs, similar to that in other species, has also been associated with decreased expression of adipose tissue PPAR-γ, a nuclear receptor that plays a key role in lipid and glucose homeostasis,19 and pharmacological activation of PPAR-γ can increase adiponectin concentrations.55 Docosapentaenoic acid can act as a ligand for PPAR-γ,52 and EPA (a precursor of DPA) increases PPAR-γ expression in adipocytes.56 Omega-3 PUFAs may increase concentrations of adiponectin by suppression of TNF-α and activation of PPAR-γ.

The direct relationship between DPA and leptin concentrations suggests that DPA may upregulate leptin production in dogs. Concentrations of DPA accounted for 19% of the range in leptin concentrations. These results are in agreement with findings in obese cats.36 However, previous studies in humans and rodents have revealed conflicting results regarding the effect of n-3 PUFAs on leptin. Investigators have found an increase,42,57,58 a decrease,59,60 or no change61,62 in leptin concentrations or leptin mRNA expression following dietary supplementation with fish oil. The reason for the variation in these findings could be related to species differences in response of leptin expression to PPAR-γ agonists. Similar to effects on adiponectin, a stimulatory effect of DPA on leptin production may be mediated through PPAR-γ activation. Investigators in 1 study49 found an increase in leptin expression in cultured canine adipocytes in response to a PPAR-γ agonist, which is in contrast to the inhibitory effect of PPAR-γ agonists on leptin expression reported in humans and rodents.63,64 It is possible that n-3 PUFAs increase leptin expression in dogs through activation of PPAR-γ.

The inverse relationship between DPA and serum triglyceride concentrations supports the lipid-lowering effect of DPA in dogs. Concentration of DPA accounted for 21% of the range of triglyceride concentrations in the dogs of the present study. These findings are in agreement with other studies of dogs,22,65 cats,36 and humans.27,66 Previous studies67 of dogs used to evaluate disease in humans and several experimental studies68–70 in healthy cats revealed no effect of n-3 PUFAs on triglyceride concentrations. These conflicting results may be explained by the differences in duration and extent of alterations in lipid concentrations among the studies. In most studies that failed to reveal an effect of n-3 PUFAs, baseline lipid concentrations were not increased. The range of triglyceride concentrations in the present study was wide, with 16% of the dogs being hypertriglyceridemic. It is possible that the lipid-lowering effect of n-3 PUFAs depends on the presence of increased baseline concentrations. The hypolipidemic effect of n-3 PUFAs is mediated through multiple mechanisms, including hepatic FA metabolism, stimulation of lipoprotein lipase activity, decreases in intestinal absorption of lipid and glucose, or stimulatory effects on adiponectin and inhibitory effects on TNF-α.71–73

No associations between any of the n-3 PUFAs and concentrations of insulin or glucose or insulin resistance were found in the present study. These findings do not provide support for a regulatory role of n-3 PUFAs in insulin sensitivity in dogs and are in general agreement with results of a previous study74 that revealed no change in insulin sensitivity in 6 healthy dogs following 6 months of dietary supplementation with fish oil. However, 1 dog with the highest concentrations of insulin in that study74 had improved insulin sensitivity following dietary supplementation. Therefore, it is possible that n-3 PUFAs may have a beneficial effect on insulin sensitivity once insulin resistance is present but do not further improve physiologically normal measures. Furthermore, the results of the present study cannot exclude the possibility for a potential effect of n-3 PUFAs on insulin sensitivity in dogs because only baseline measures of insulin sensitivity were evaluated. In addition, the inclusion of dogs with variable body condition in the present study increased the variation in serum concentrations of insulin and glucose and therefore reduced the power of the present study to reveal any existing association between n-3 PUFAs and measures of insulin sensitivity.

Adipokines and triglyceride were primarily associated with DPA in the present study, rather than with other long-chain n-3 PUFAs (EPA and DHA) or an n-3 PUFA of shorter chain length (ALA). The absence of associations with n-3 PUFAs other than DPA may have been related to the skewed distribution of the concentrations of these FAs, in contrast to the normally distributed concentration of DPA. Alternatively, the fact that associations of the outcome variables were mainly with DPA may be of biological importance. A previous study75 on lipid metabolism in mice revealed intermediate effects of DPA between those of EPA and DHA, and the authors concluded that the beneficial effects of DPA are not superior to those of EPA or DHA, in contrast to findings of the present study. Docosapentaenoic acid is the main metabolite of ALA in cell membranes; therefore, it may serve as an important circulating or tissue reservoir for EPA or DHA synthesis. A study76 on dietary supplementation with ALA in dogs revealed enrichment of the phospholipid and triglyceride fractions (but not the cholesteryl-ester fraction) with DPA following dietary supplementation. This indicated tissue conservation of DPA, which may then serve as a substrate for EPA or DHA synthesis in the tissues. Therefore, the associations with DPA detected in the present study may be indicative of an effect of long-chain n-3 PUFAs in general. The lack of significant associations between adiponectin or leptin concentrations and ALA concentrations suggested that potential beneficial biological effects of n-3 PUFAs are attributable to the long-chain n-3 PUFAs. The fact that the effect of ALA on triglyceride concentrations is opposite to that for DPA is not simple to explain, but it is possible that a low ALA concentration is a marker for higher DPA concentrations as a result of the conversion of ALA to DPA.

Associations with serum concentrations of n-3 PUFAs were detected in the study reported here. Although ALA is an essential FA and its serum concentrations are determined by the composition of the diet, conversion of ALA to longer-chain n-3 PUFAs may be influenced by other factors. In addition, dogs were receiving nonsupplemented, nutritionally complete, and balanced diets. Therefore, the potential effect of extreme dietary amounts of n-3 PUFAs was not evaluated in the present study.

The association between percentage of body fat and serum concentrations of leptin was significant after adjusting for potential confounders, and changes in percentage of body fat accounted for 69% of the range of leptin concentrations. In contrast, there was no significant association between percentage of body fat and serum concentrations of adiponectin after adjustment for the same confounders. These findings indicated that adiposity is a strong independent determinant of circulating concentrations of leptin but not adiponectin in dogs. Previous studies that addressed the association between body condition and adiponectin concentrations in dogs revealed conflicting results, which consisted of no association11–13 (in agreement with the findings of the present study) or a negative association3,9 (similar to findings in other species). These inconsistent findings could result from the strong association between n-3 PUFAs and serum concentrations of adiponectin revealed in the present study. Potential differences in the variation of n-3 PUFAs in dogs among the various studies could explain the conflicting reports. A wide range of n-3 PUFA concentrations would be expected to induce higher variation in serum concentrations of adiponectin, which would render a weak effect of body condition on adiponectin concentrations undetectable; in contrast, a narrow range of n-3 PUFA concentrations might facilitate detection of this effect. No interactions between percentage of body fat and n-3 PUFA concentrations were revealed in any of the analyses, which indicated that the associations between percentage of body fat and serum concentrations of adiponectin, leptin, insulin, glucose, and triglyceride and insulin resistance were similar across the range of body conditions.

Age was significantly associated with serum concentrations of leptin and adiponectin following adjustment for potential confounders. Age had a positive effect on serum concentrations of leptin, accounting for 19% of the range, and a negative effect on serum concentrations of adiponectin, accounting for 37% of the range. In another study77 of dogs, investigators found a positive association between age and leptin concentrations; however, this association was thought to be attributable to the lower content of visceral fat in puppies < 1 year old. This cannot explain the association found in the present study because only dogs > 1 year old were included. A similar effect of age on the increase in leptin concentrations has been reported in cats36 and rodents78,79; in the latter, it is thought to result from decreased leptin signaling in the hypothalamus as a consequence of aging and the development of leptin resistance. Previous studies regarding the effect of age on concentrations of adiponectin are conflicting. No effect was found in cats,36 whereas in humans and rodents, concentrations of adiponectin were found to not change79,80 or to increase81–83 with age. The human subjects in the later studies were older, and the increase in concentrations of adiponectin was suggested to result from a decrease in renal function as a consequence of aging.82 This may provide at least a partial explanation for the difference in findings for the dogs of the present study, given that only 8 dogs were > 10 years old. Investigators in another study84 found an interaction between sex and age (adiponectin concentrations increased with age in males but not in females). Such an interaction was not identified in the present study.

For the study reported here, we concluded that DPA but not other n-3 PUFAs (ie, ALA, EPA, and DHA) is directly associated with serum concentrations of adiponectin and leptin and inversely associated with serum concentrations of triglyceride in healthy dogs. These findings suggest that n-3 PUFAs may have a regulatory role on production of these 2 adipokines and support the known hypolipidemic effect of n-3 PUFAs in dogs. Docosapentaenoic acid n-3 may be the primary n-3 PUFA responsible for these potential effects, or serum concentrations of DPA may serve as an indicator for a general effect of n-3 PUFAs.

ABBREVIATIONS

ALA

α-Linolenic acid

BCS

Body condition score

CI

Confidence interval

DHA

Docosahexaenoic acid

DPA

Docosapentaenoic acid

EPA

Eicosapentaenoic acid

FA

Fatty acid

n-3

PUFA Omega-3 polyunsaturated fatty acid

PPAR

Peroxisome proliferator-activated receptor

TNF

Tumor necrosis factor

a.

Burkholder W. Body composition of dogs determined by carcass composition analysis, deuterium oxide dilution, subjective and objective morphometry, and bioelectrical impedance. PhD dissertation, Veternary Medical Services Department, Virginia Polytechnic Institute and State University, Blacksburg, Va, 1994.

b.

Canine adiponectin ELISA kit, Millipore Corp, St Charles, Mo.

c.

Canine leptin ELISA kit, Millipore Corp, St Charles, Mo.

d.

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

e.

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

f.

Clarus 500 gas chromatograph, PerkinElmer, Shelton, Conn.

g.

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

h.

Nu-Check Prep Inc, Elysian, Minn.

i.

HOMA calculator, version 2.2.2, Diabetes Trial Unit, University of Oxford, Oxford, England.

j.

SPSS, version 19.0 for Windows, SPSS Inc, Chicago, Ill.

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