Exercise induces favorable metabolic changes in white adipose tissue preventing high-fat diet obesity.

Diet and/or exercise are cost effective interventions to treat obesity. However, it is unclear if the type of exercise undertaken can prevent the onset of obesity and if it can act through different effects on fat depots. In this study we did not allow obesity to develop so we commenced the high-fat diet (HFD) and exercise programs concurrently and investigated the effect of endurance exercise (END) and high-intensity interval training (HIIT) on changes in cellular adipogenesis, thermogenesis, fibrosis, and inflammatory markers in three different fat depots, on a HFD and a chow diet. This was to assess the effectiveness of exercise to prevent the onset of obesity-induced changes. Mice fed with chow or HFD (45% kcal fat) were trained and performed either END or HIIT for 10 weeks (3 x 40 min sessions/week). In HFD mice, both exercise programs significantly prevented the increase in body weight (END: 17%, HIIT: 20%), total body fat mass (END: 46%, HIIT: 50%), increased lean mass as a proportion of body weight (Lean mass/BW) by 14%, and improved insulin sensitivity by 22%. Further evidence of the preventative effect of exercise was seen significantly decreased markers for adipogenesis, inflammation, and extracellular matrix accumulation in both subcutaneous adipose tissue (SAT) and epididymal adipose tissue (EPI). In chow, no such marked effects were seen with both the exercise programs on all the three fat depots. This study establishes the beneficial effect of both HIIT and END exercise in preventing metabolic deterioration, collagen deposition, and inflammatory responses in fat depots, resulting in an improved whole body insulin resistance in HFD mice.

The effect of TGFß1 on thermogenic markers is dependent on the degree of adipocyte differentiation.

Transforming growth factor ß (TGFß) a multifunctional cytokine is known to regulate cell proliferation, differentiation, migration and survival. Although there is variable expression of modulators of TGFß action during differentiation, a differential effect on fat cell metabolism at the different stages of adipocyte differentiation was unclear. In the present study, 3T3L1 cells were used as an in vitro model to study the effect of TGFß on adipogenic and thermogenic markers at various stages of preadipocyte to mature adipocyte differentiation. As in our earlier studies on the effect of TGFß on CEBP's, we used a standard differentiation mix, and one with the addition of rosiglitazone. RhTGFß1 was added to undifferentiated adipocytes (preadipocytes) and to adipocytes at day 0 (commitment stage) as well as day 10 (terminal differentiation). Cellular responses in terms of Pref1, PPARγ, TLE3, PGC1α, PRDM16, UCP1 and UCP2 mRNA levels and selected protein products, were determined. Increases in PPARγ, PRDM16, UCP1 and UCP2 mRNA and decreases in Pref1 are good indicators of successful differentiation. The early addition of rhTGFß1 during commitment stage decreased PPARγ, PRDM16, TLE3, UCP1 and UCP2 mRNA and decreased PRDM16 protein consistent with our earlier report on the inhibition of CEBP's by TGFß and CCN2. The addition of rhTGFß1 to mature adipocyte at day 10 increased UCP1 mRNA and increased PRDM16 and UCP1 proteins. In the present study, our results suggest that TGFß1 added late enhances the thermogenic potential of mature cells and causes 3T3L1 cells to differentiate to resemble brown or beige rather than white adipose tissue.

Skeletal muscle adiponectin induction depends on diet, muscle type/activity, and exercise modality in C57BL/6 mice.

Changes in skeletal muscle adiponectin induction have been described in obesity and exercise. However, whether changes are consistent across muscle types and with different exercise modalities, remain unclear. This study compared the effects of diet and two isocaloric training programs on adiponectin induction and its regulators in three muscles: quadriceps (exercising/glycolytic-oxidative), gastrocnemius (exercising/glycolytic), and masseter (nonexercising/glycolytic). Ten-week-old male C57BL/6 mice were fed a high-fat diet (HFD) (45% fat) or standard CHOW diet (12% fat) ad libitum and underwent one of two training regimes: (1) constant-moderate training (END), or (2) high intensity interval training (HIIT) for 10 weeks (3 × 40 min sessions/week). Chow and HFD-fed untrained mice were used as control. Compared with Chow, HFD induced an increase in protein levels of low-molecular weight (LMW) adiponectin in gastrocnemius and masseter (~2-fold; P < 0.05), and a decrease of high-molecular weight adiponectin (HMW-most bioactive form) in quadriceps (~0.5-fold; P < 0.05). Only END prevented these changes (P < 0.05). HFD induced a decrease of adiponectin receptor 1 (AdipoR1) protein in exercising muscles of untrained mice (~0.5-0.8-fold; P < 0.05); notably, END also decreased AdipoR1 protein levels in lean and HFD mice. This type of training also normalized HFD-driven mRNA changes found in some adiponectin downstream factors (sirtuin 1, Pgc-1a, and Ucp2) in the three muscles tested. Our results indicate that diet, muscle type/activity, and exercise modality influences muscle adiponectin profile, and some of its mediators. These parameters should be taken into consideration when investigating this endocrine response of the skeletal muscle, particularly in the context of obesity and metabolic disorders.

Novel lavendamycin analogues as antitumor agents: synthesis, in vitro cytotoxicity, structure-metabolism, and computational molecular modeling studies with NAD(P)H:quinone oxidoreductase 1.

Novel lavendamycin analogues with various substituents were synthesized and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. Pictet-Spengler condensation of quinoline- or quninoline-5,8-dione aldehydes with tryptamine or tryptophans yielded the lavendamycins. Metabolism studies with recombinant human NQO1 revealed that addition of NH2 and CH2OH groups at the quinolinedione-7-position and indolopyridine-2'-position had the greatest positive impact on substrate specificity. The best and poorest substrates were 37 (2'-CH2OH-7-NH2 derivative) and 31 (2'-CONH2-7-NHCOC3H7-n derivative) with reduction rates of 263 +/- 30 and 0.1 +/- 0.1 micromol/min/mg NQO1, respectively. Cytotoxicity toward human colon adenocarcinoma cells was determined for the lavendamycins. The best substrates for NQO1 were also the most selectively toxic to the NQO1-rich BE-NQ cells compared to NQO1-deficient BE-WT cells with 37 as the most selective. Molecular docking supported a model in which the best substrates were capable of efficient hydrogen-bonding interactions with key residues of the active site along with hydride ion reception.