Restoration of adipose function in obese glucose-tolerant men following pioglitazone treatment is associated with CCAAT enhancer-binding protein β up-regulation

Abstract

Obese AT (adipose tissue) exhibits increased macrophage number. Pro-inflammatory CD16+ peripheral monocyte numbers are also reported to increase with obesity. The present study was undertaken to simultaneously investigate obesity-associated changes in CD16+ monocytes and ATMs (AT macrophages). In addition, a pilot randomized placebo controlled trial using the PPAR (peroxisome-proliferator-activated receptor) agonists, pioglitazone and fenofibrate was performed to determine their effects on CD14+/CD16+ monocytes, ATM and cardiometabolic and adipose dysfunction indices. Obese glucose-tolerant men (n=28) were randomized to placebo, pioglitazone (30 mg/day) and fenofibrate (160 mg/day) for 12 weeks. A blood sample was taken to assess levels of serum inflammatory markers and circulating CD14+/CD16+ monocyte levels via flow cytometry. A subcutaneous AT biopsy was performed to determine adipocyte cell surface and ATM number, the latter was determined via assessment of CD68 expression by IHC (immunohistochemistry) and real-time PCR. Subcutaneous AT mRNA expression of CEBPβ (CCAAT enhancer-binding protein β), SREBP1c (sterol-regulatory-element-binding protein 1c), PPARγ2, IRS-1 (insulin receptor substrate-1), GLUT4 (glucose transporter type 4) and TNFα (tumour necrosis factor α) were also assessed. Comparisons were made between obese and lean controls (n=16) at baseline, and pre- and post-PPAR agonist treatment. Obese individuals had significantly increased adipocyte cell surface, percentage CD14+/CD16+ monocyte numbers and ATM number (all P=0.0001). Additionally, serum TNF-α levels were significantly elevated (P=0.017) and adiponectin levels reduced (total: P=0.0001; high: P=0.022) with obesity. ATM number and percentage of CD14+/CD16+ monocytes correlated significantly (P=0.05). Pioglitazone improved adiponectin levels significantly (P=0.0001), and resulted in the further significant enlargement of adipocytes (P=0.05), without effect on the percentage CD14+/CD16+ or ATM number. Pioglitazone treatment also significantly increased subcutaneous AT expression of CEBPβ mRNA. The finding that improvements in obesity-associated insulin resistance following pioglitazone were associated with increased adipocyte cell surface and systemic adiponectin levels, supports the centrality of AT to the cardiometabolic derangement underlying the development of T2D (Type 2 diabetes) and CVD (cardiovascular disease).

Innate and ozone-induced airway hyperresponsiveness in obese mice: role of TNF-α

“…Serum TNF-␣ is elevated in obesity (22,36,45,58), including in Cpe fat vs. WT mice (58), and TNF-␣ can induce many of the other serum cytokines and chemokines that are also elevated in the serum in obesity (2,15,30,33,41,47,58). Our data indicate increases in serum concentrations of many cytokines and chemokines in Cpe fat vs. WT mice (Fig.…”

“…The chronic, low-grade, systemic inflammation that characterizes obesity promotes other obesity-related conditions (18,23,42,54) and may also play a role in the etiology of obesity-related asthma (26,49,53). Circulating TNF-␣ is increased both in obese humans and obese mice (22,36,45,58) and may be of relevance for asthma, since exogenous administration of TNF-␣ has the capacity to induce AHR (55). TNF-␣ also has the capacity to induce many of the other cytokines and chemokines whose circulating concentrations are elevated in obesity, including MCP-1, G-CSF, IL-9, IP-10, IL-17A, and KC (2,15,30,33,41,47,58).…”

Effects of Pioglitazone on Insulin Sensitivity and Serum Lipids in Obese Cats

“…Relief of compensatory hyperinsulinemia also occurred with the more potent experimental TZD darglitazone in obese cats,8 and is a predictable outcome of TZD administration in obese humans and rodents 18, 20. In addition, insulin sensitization with pioglitazone enhanced NEFA suppression during the first 90 min of IVGTT; potential mechanisms for this change include greater inhibition of lipolysis, increased NEFA uptake, or some combination of the two.…”

“…In addition, it is encouraging with respect to the therapeutic potential of pioglitazone in diabetic cats, and perhaps in cats with hepatic lipidosis. In humans and rodents, the glycemic effects of the TZDs are more pronounced in diabetic than in obese individuals,18, 19 and the same doses of pioglitazone that increase insulin sensitivity in human obesity lower glucose and NEFA concentrations in type 2 diabetics 9, 20. Thus, it is possible that the insulin sensitization produced by pioglitazone in the obese cats would be manifest as a favorable impact on glucose and NEFA concentrations in diabetic cats.…”

“…A similar mechanism may have been responsible for the decrease in triglycerides in the obese cats. With regard to cholesterol, the effects of pioglitazone differ between humans and cats: pioglitazone increases high‐density lipoprotein (HDL) cholesterol in humans, but does not affect total cholesterol 20, 29. This difference may relate to the fact that (1) cats carry most of their cholesterol in HDL, and (2) activity of cholesteryl ester transfer protein, which catalyzes the exchange of cholesterol between HDL and other lipoproteins, appears to be very low in cats 30.…”