Effects of Pioglitazone on Adipose Tissue Remodeling Within the Setting of Obesity and Insulin Resistance

Abstract

Obesity and dysfunctional energy partitioning can lead to the development of insulin resistance and type 2 diabetes. The antidiabetic thiazolidinediones shift the energy balance toward storage, leading to an increase in whole-body adiposity. These studies examine the effects of pioglitazone (Pio) on adipose tissue physiology, accumulation, and distribution in female Zucker (fa/fa) rats. Pio treatment (up to 28 days) decreased the insulin-resistant and hyperlipidemic states and increased food consumption and whole-body adiposity. Magnetic resonance imaging (MRI) analysis and weights of fat pads demonstrated that the increase in adiposity was not only limited to the major fat depots but also to fat deposition throughout the body. Adipocyte sizing profiles, fat pad histology, and DNA content show that Pio treatment increased the number of small adipocytes because of both the appearance of new adipocytes and the shrinkage and/or disappearance of existing mature adipocytes. The remodeling was time dependent, with new small adipocytes appearing in clusters throughout the fat pad, and accompanied by a three- to fourfold increase in citrate synthase and fatty acid synthase activity. The appearance of new fat cells and the increase in fat mass were depot specific, with a rank order of responsiveness of ovarian > retroperitoneal > subcutaneous. This differential depot effect resulted in a redistribution of the fat mass in the abdominal region such that there was an increase in the visceral:subcutaneous ratio, as confirmed by MRI analysis. Although the increased adiposity is paradoxical to an improvement in insulin sensitivity, the quantitative increase of adipose mass should be viewed in context of the qualitative changes in adipose tissue, including the remodeling of adipocytes to a smaller size with higher lipid storage potential. This shift in energy balance is likely to result in lower circulating free fatty acid levels, ultimately improving insulin sensitivity and the metabolic state.

Human adenovirus Ad-36 induces adipogenesis via its E4 orf-1 gene

“…Increased proliferation, differentiation and activation of PI3K in adipocytes results in greater insulin sensitivity. 8,37 Therefore, the ability of Ad-36 to induce adipogenesis may be important for influencing insulin sensitivity. Indeed, Ad-36 infection of rats increased by several fold adipose tissue expression of many adipogenic genes including PPARg and C/EBP-b, reduced fasting insulin levels to 54% and significantly improved the HOMA index.…”

“…Pharmaceutical efforts have exploited the manipulation of adipogenesis to improve the metabolic profiles in these patients. For instance, adipogenesis induced by TZDs is considered to lower circulating free fatty acids levels, ultimately contributing to improved insulin sensitivity in type 2 diabetes 8,9 even the in presence of obesity. 38,39 On the other hand, insulin resistance of lipodystrophy [40][41][42] has been unsuccessfully treated with TZD.…”

“…[4][5][6] On the other hand, adequate lipid storage in the adipose tissue, 7 or induction of adipogenesis improves insulin sensitivity. [8][9][10] Therefore, understanding the regulation of adipocyte differentiation by cellular and extracellular factors is crucial for better management of chronic conditions such as obesity, insulin resistance and lipodystrophy.…”

Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

“…Thiazolidinediones improve insulin sensitivity both in man and in different animal models of insulin resistance [3,4]. The improvement in insulin resistance is, at least in rodent models, accompanied by a remodelling of the adipose tissue, where large adipocytes are replaced by an increased recruitment of small and more insulin-sensitive cells [5,6]. However, to what extent this occurs in human adipose tissue is still not clear [7].…”

Long-term pioglitazone treatment enhances lipolysis in rat adipose tissue

“…It is generally believed that TZDs ameliorate lipotoxicity and insulin resistance at least in part by reducing circulating levels of nonesterified fatty acids (NEFA). [1][2][3] Circulating levels of NEFA are influenced by multiple factors, including the rates of lipolysis and fatty acid reesterification in adipose tissue, and by cellular uptake and metabolism of fatty acids. There are conflicting results regarding the effects of TZDs on the adipose tissue release of NEFA.…”