Improvement in insulin resistance and reduction in plasma inflammatory adipokines after weight loss in obese dogs

Abstract

Obesity is now a major disease of dogs, predisposing to numerous disorders including diabetes mellitus. Adipocytes are active endocrine cells, and human obesity is characterized by derangements in inflammatory adipokine production. However, it is unclear as to whether similar changes occur in dogs. The purpose of the current study was to assess insulin sensitivity and inflammatory adipokine profiles in dogs with naturally occurring obesity and to investigate the effect of subsequent weight loss. Twenty-six overweight dogs were studied, representing a range of breeds and both sexes. All dogs underwent a weight loss program involving diet and exercise. Body fat mass was measured by dual-energy x-ray absorptiometry; plasma concentrations of insulin, glucose, and a panel of inflammatory adipokines (including acute-phase proteins, cytokines, and chemokines) were also analyzed. Body fat mass before weight loss was positively correlated with both plasma insulin concentrations (Kendall τ = 0.30, P = 0.044) and insulin:glucose ratio (Kendall τ = 0.36, P = 0.022), and both decreased after weight loss (P = 0.0037 and 0.0063, respectively). Weight loss also led to notable decreases in plasma tumor necrosis factor-α (TNF-α), haptoglobin, and C-reactive protein concentrations (P < 0.05 for all), suggesting improvement of a subclinical inflammatory state associated with obesity. This study has demonstrated that in obese dogs, insulin resistance correlates with degree of adiposity, and weight loss improves insulin sensitivity. Concurrent decreases in TNF-α and adipose tissue mass suggest that in dogs, as in humans, this adipokine may be implicated in the insulin resistance of obesity.

Introduction

Obesity is defined as a disease in which excess body fat has accumulated such that health may be adversely affected [1]. Obese humans are known to suffer from several associated clinical conditions including hypertension, coronary heart disease, certain cancers (eg, breast, ovarian, prostate), osteoarthritis, respiratory disease, and reproductive disorders [1]. Similarly, obesity has detrimental effects on the health of dogs, with disease associations including orthopedic diseases, respiratory disease, urinary tract disorders, and decreased longevity [2], [3], [4]. However, a possible association between obesity and cancer is controversial is dogs, with one study suggesting an association [2], whilst another suggested no relationship [5].

In humans, the most important disease association is that of the metabolic syndrome, a group of metabolic and vascular disorders, which increase the risk of an individual developing type 2 diabetes and cardiovascular disease [6]. The risk of developing diabetes increases with increasing body mass index (BMI); individuals with a BMI > 30 kg/m² are 10 times more likely to develop type 2 diabetes than those with a BMI < 25 kg/m² [7]. In contrast, dogs more commonly suffer from a form of diabetes resembling type 1 diabetes in man [8], [9], [10], and although common, its pathogenesis is poorly understood [11], [12], [13]. Although dogs do not commonly suffer from type 2 diabetes [11], [12], [13], a previous study has reported an association between canine diabetes and excess body weight [2]. The reason for such an association is not clear but may be owing to insulin resistance, which can be induced experimentally in dogs through dietary manipulation [14], [15], [16], [17]. Further, lifelong dietary energy restriction has been shown to improve insulin sensitivity and glucose tolerance [18], and a relationship between obesity, glucose tolerance, and insulin response was reported in one study of dogs with naturally occurring diabetes [19]. However, in that study, the degree of excess weight was estimated subjectively using breed standards, which is a notoriously unreliable method for quantifying adiposity. Therefore, further studies are clearly required to clarify the link between insulin resistance in naturally occurring canine obesity.

White adipose tissue (WAT) has recently been recognized as an active endocrine organ that is capable of secreting a wide range of hormones and protein factors, collectively termed adipokines [20], [21]. Of particular note is the range of cytokines, chemokines, and other inflammation-related proteins secreted by WAT, such that a state of chronic low-grade systemic inflammation is now known to exist in obesity [22], [23]. Systemic concentrations of acute-phase proteins (eg, C-reactive protein [CRP], haptoglobin) and pro-inflammatory cytokines (eg, IL-6 and tumor necrosis factor-α [TNFα]) are elevated in obese individuals [24]. Since adipose tissue is an important source of these factors [23], this organ system may contribute significantly to the elevated circulating concentrations [23], providing a link between obesity, insulin resistance, and the metabolic syndrome in humans [25], [26]. Further, weight loss in these subjects has been shown to reverse this low-grade inflammatory state and to improve insulin sensitivity [27].

Our recent work has demonstrated that genes encoding key inflammatory adipokines are expressed in canine WAT samples and in canine adipocytes differentiated in culture [28], [29]. However, studies examining adipokine profiles in canine obesity and associated disease, including insulin resistance, are limited. Therefore, the purpose of the current study was to assess insulin sensitivity and inflammatory adipokine profiles in dogs with naturally occurring obesity and to determine the effect of subsequent weight loss.