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Treatment of subjects who are obese/insulin resistant with the β3AR agonist mirabegron resulted in increased beige adipose tissue, without a change in brown adipose tissue (BAT), along with an improvement in glucose tolerance, HbA1c, and an increase in type 1 fibers in skeletal muscle. Pioglitazone has been demonstrated to increase beiging, and it has been demonstrated that combination of a thiazolidinedione with a β3AR agonist further increased beige adipocyte markers in vitro. The goal of this study was to determine whether combination therapy with pioglitazone and mirabegron would further increase beiging, BAT volume or activity, or skeletal muscle fiber type switching, and improve glucose homeostasis more than each drug separately. We randomized obese and insulin-resistant (IR) research participants to mirabegron (50 mg/day), pioglitazone (30 mg/day), or combination treatment groups. Adipose and muscle tissue biopsies and PET-CT scans were performed at baseline and after 10 weeks of treatment. Mitochondrial bioenergetics were determined in purified mitochondria from adipose tissue. Although mirabegron and pioglitazone treatment significantly induced SC WAT beiging separately, the combination of the two drugs resulted in less beiging than mirabegron treatment alone, and did not increase mitochondrial uncoupling. Furthermore, neither pioglitazone nor combination therapy increased BAT or fiber-type switching to type 1 fibers. Although each drug improved glucose homeostasis, the effect of the combination was not significantly additive. Analysis of mRNA expression revealed that pioglitazone or combination treatment induced the expression of p107, which promotes white versus brown adipose gene expression, suggesting a mechanism for inhibition of mirabegron-induced beiging by pioglitazone. These results suggest that pioglitazone inhibits mirabegron-induced beiging and does not augment other beneficial effects of mirabegron treatment. Disclosure P.A. Kern: None. H. Memetimin: None. B. Zhu: None. A.L. Confides: None. Z. Johnson: None. H.J. Vekaria: None. P. Westgate: None. P.G. Sullivan: None. E.E. Dupont-Versteegden: None. B. Finlin: None. Funding National Institutes of Health (DK112282)

Brown adipose tissue (BAT) is associated with improved metabolic homeostasis in humans, and studies in rodents indicate that subcutaneous white adipose tissue (SC WAT) beiging, which involves increased uncoupling protein 1 (UCP1) expression, also is associated with improved metabolism. The goal of this study was to determine the ability of mirabegron (a β3AR agonist), pioglitazone (a thiazolidinedione), or a combination of the drugs to induce brown and beige adipose tissue and to determine the effects on glucose and lipid homeostasis. We randomized obese, insulin-resistant (IR) research participants to mirabegron (50 mg/day), pioglitazone (30 mg/day), or combination therapy treatment groups. Euglycemic clamping, oral glucose tolerance tests, adipose tissue biopsies, and PET-CT scans were performed at baseline and after 10 weeks of treatment. Mirabegron improved glucose homeostasis (reduced HbA1c and improved oral glucose tolerance) to a similar extent as pioglitazone without side effects or weight gain. Although mirabegron treatment increased insulin sensitivity, the effect size was much smaller than pioglitazone, yet mirabegron treatment significantly increased the insulinogenic and disposition indexes, suggesting that a major part of the mechanism of mirabegron action involved improving β-cell function. Mirabegron treatment consistently induced SC WAT beiging as evidenced by increased UCP1 expression (2.4 fold increase; P Disclosure B. Finlin: None. H. Memetimin: None. A.L. Confides: None. B. Zhu: None. Z.R. Johnson: None. E.E. Dupont-Versteegden: None. P.A. Kern: None. Funding National Institutes of Health (R01DK112282)

IκB kinase β (IKKβ), a central coordinator of inflammatory responses through activation of nuclear factor-κB (NF-κB), has been implicated as a critical molecular link between inflammation and metabolic disorders; however, the role of adipocyte IKKβ in obesity and related metabolic disorders remains elusive. Here we report an essential role of IKKβ in the regulation of adipose remodeling and adipocyte survival in diet-induced obesity. Targeted deletion of IKKβ in adipocytes does not affect body weight, food intake, and energy expenditure but results in an exaggerated diabetic phenotype when challenged with a high-fat diet (HFD). IKKβ-deficient mice have multiple histopathologies in visceral adipose tissue, including increased adipocyte death, amplified macrophage infiltration, and defective adaptive adipose remodeling. Deficiency of IKKβ also leads to increased adipose lipolysis, elevated plasma free fatty acid (FFA) levels, and impaired insulin signaling. Mechanistic studies demonstrated that IKKβ is a key adipocyte survival factor and that IKKβ protects murine and human adipocytes from HFD- or FFA-elicited cell death through NF-κB–dependent upregulation of antiapoptotic proteins and NF-κB–independent inactivation of proapoptotic BAD protein. Our findings establish IKKβ as critical for adipocyte survival and adaptive adipose remodeling in obesity.

Fish oils (FOs) have anti-inflammatory effects and lower serum triglycerides. This study examined adipose and muscle inflammatory markers after treatment of humans with FOs and measured the effects of ω-3 fatty acids on adipocytes and macrophages in vitro. Insulin-resistant, nondiabetic subjects were treated with Omega-3-Acid Ethyl Esters (4 g/day) or placebo for 12 weeks. Plasma macrophage chemoattractant protein 1 (MCP-1) levels were reduced by FO, but the levels of other cytokines were unchanged. The adipose (but not muscle) of FO-treated subjects demonstrated a decrease in macrophages, a decrease in MCP-1, and an increase in capillaries, and subjects with the most macrophages demonstrated the greatest response to treatment. Adipose and muscle ω-3 fatty acid content increased after treatment; however, there was no change in insulin sensitivity or adiponectin. In vitro, M1-polarized macrophages expressed high levels of MCP-1. The addition of ω-3 fatty acids reduced MCP-1 expression with no effect on TNF-α. In addition, ω-3 fatty acids suppressed the upregulation of adipocyte MCP-1 that occurred when adipocytes were cocultured with macrophages. Thus, FO reduced adipose macrophages, increased capillaries, and reduced MCP-1 expression in insulin-resistant humans and in macrophages and adipocytes in vitro; however, there was no measureable effect on insulin sensitivity.