Activation of UCPs gene expression in skeletal muscle can be independent on both circulating fatty acids and food intake. Involvement of ROS in a model of mouse cancer cachexia

Implantation of a fast growing tumour to mice (Lewis lung carcinoma) resulted in a clear cachectic state characterized by a profound muscle wasting. This was accompanied by a significant increase in both UCP2 and UCP3 gene expression in skeletal muscle and heart. Interestingly, this increase in gene expression was not linked to a rise in circulating fatty acids or in a decrease in food intake, as previously reported in other pathophysiological states. These results question the concept that hyperlipaemia is the only factor controlling UCP gene expression in different pathophysiological conditions. In addition, the present work suggests that UCPs might participate in a counter-regulatory mechanism to lower the production of ROS.     

Browning of white adipose tissue induced by the ß3 agonist CL-316,243 after local and systemic treatment - PK-PD relationship

Transformation of white adipose tissue (WAT) to a brown adipose tissue-like (BAT-like) phenotype has emerged as an attractive approach against obesity e.g. using g ß3 adrenergic receptor agonists. These could however, produce side-effects following systemic exposure. The present study explored the possibility of local use of CL-316,243 - a selective ß3 agonist - to circumvent this problem.Rats treated s.c. for 2?weeks (0.3 and 1?mg/kg) showed decreased inguinal fat pad (IFP) weight/volume, increased UCP-1 staining and expressed BAT-like features in H&E stained micrographs. Interscapular BAT increased in weight/volume. In contrast, local treatment into the IFP was not efficacious in terms of weight/volume, despite slight increases in UCP-1 staining and changes in histological features.After local treatment, the exposure of the IFP was lower than after systemic treatment. In turn higher local doses (0.5 and 5?mg/ml) were then tested which produced a strong trend for decreased volume of the IFP, a significant increase in UCP-1 staining, and also a decrease in adipocytes size but increased number. However, after this treatment the systemic exposure was in the same range as following systemic treatment. In conclusion, we saw no evidence for the possibility of converting inguinal WAT to a BAT-phenotype solely through local activation of ß3 receptors.This is in concert with our in vitro experiments which detected direct effects of PPARγ agonists at the gene/protein expression and functional level, but were unable to detect any effect of CL-316,243.     

Fat accumulation in differentiated brown adipocytes is linked with expression of Hox genes

Homeobox (Hox) genes are involved in body plan of embryo along the anterior–posterior axis. Presence of several Hox genes in white adipose tissue (WAT) and brown adipose tissue (BAT) is indicative of involvement of Hox genes in adipogenesis. We propose that differentiation inducing agents viz. isobutyl-methyl-xanthine (IBMX), indomethacin, dexamethasone (DEX), triiodothyronine (T3) and insulin may regulate differentiation in brown adipose tissue through Hox genes. In vitro culture of brown fat stromalvascular fraction (SVF) in presence or absence of differentiation inducing agents was used for establishing relationship between fat accumulation in differentiated adipocytes and expression of Hox genes. Relative expression of Pref1, UCP1 and Hox genes was determined in different stages of adipogenesis. Presence or absence of IBMX, indomethacin and DEX during differentiation of proliferated pre-adipocytes resulted in marked differences in expression of Hox genes and lipid accumulation. In presence of these inducing agents, lipid accumulation as well as expression of HoxA1, HoxA5, HoxC4 & HoxC8 markedly enhanced. Irrespective of presence or absence of T3, insulin down regulates HoxA10. T3 results in over expression of HoxA5, HoxC4 and HoxC8 genes, whereas insulin up regulates expression of only HoxC8. Findings suggest that accumulation of fat in differentiated adipocytes is linked with expression of Hox genes.     

Global deletion of lipocalin 2 does not reverse high-fat diet-induced obesity resistance in stearoyl-CoA desaturase-1 skin-specific knockout mice

Over the past century, obesity has developed into a paramount health issue that affects millions of people worldwide. Obese individuals have an increased risk to develop other metabolic disorders, such as insulin resistance and atherosclerosis, among others. Previously we determined that mice lacking stearoyl-CoA desaturase-1 (SCD1) enzyme specifically in the skin (SKO) were lean and protected from high-fat diet induced adiposity. Additionally, lipocalin 2 (Lcn2) mRNA was found to be 27-fold higher in the skin of SKO mice compared to control mice. Given reports suggesting that Lcn2 plays a role in protection against diet-induced weight gain, adiposity and insulin resistance, we hypothesized that deletion of Lcn2 alongside the skin-specific SCD1 deficiency would diminish the obesity resistance observed in SKO mice. To test this, we developed mice lacking SCD1 expression in the skin and also lacking Lcn2 expression globally and surprisingly, these mice did not gain significantly more weight than the SKO mice under high-fat diet conditions. Therefore, we conclude that Lcn2 does not mediate the protection against high-fat diet-induced adiposity observed in SKO mice.     

Plasma acylcarnitines inadequately reflect tissue acylcarnitine metabolism

Acylcarnitines have been linked to obesity-induced insulin resistance. However the majority of these studies have focused on acylcarnitines in plasma. It is currently unclear to what extent plasma levels of acylcarnitines reflect tissue acylcarnitine metabolism. We investigated the correlation of plasma acylcarnitine levels with selected tissue acylcarnitines as measured with tandem mass spectrometry, in both fed and fasted BALB/cJ (BALB) and C57BL/6N (Bl6) mice. Fasting affected acylcarnitine levels in all tissues. These changes varied substantially between the different tissue compartments. No significant correlations were found between plasma acylcarnitine species and their tissue counterparts in both mouse strains, with the exception of plasma C4OH-carnitine in BALB mice. We suggest that this lack of correlation is due to differences in acylcarnitine turnover rates between plasma and tissue compartments and the fact that the plasma acylcarnitine profile is a composition of acylcarnitines derived from different compartments. Therefore, plasma acylcarnitine levels do not reflect tissue levels and should be interpreted with caution. A focus on tissue acylcarnitine levels is warranted in metabolic studies.     

IL-33, a recently identified interleukin-1 gene family member, is expressed in human adipocytes

Inflammation occurs in adipose tissue in obesity. We have examined whether IL-33, a recently identified IL-1 gene family member, and its associated receptors are expressed in human adipocytes. IL-33, IL-1RL1 and IL-1RAP gene expression was observed in human visceral white fat, in preadipocytes and in adipocytes (SGBS cells). Treatment with TNFα for 24 h induced a 6-fold increase in IL-33 mRNA level in preadipocytes and adipocytes. Time-course studies with adipocytes showed that the increase in IL-33 mRNA with TNFα was maximal (>55-fold) at 12 h. This response was markedly different to IL-1β (peak mRNA increase at 2 h; 5.4-fold) and 1L-18 (peak mRNA increase at 6 h; >1500-fold). Exposure of adipocytes to hypoxia (1% O₂, 24 h) did not alter IL-33 mRNA level; in preadipocytes, however, there was a 3-fold increase. Human adipocytes and preadipocytes express IL-33, but the various IL-1 family members exhibit major differences in responsiveness to TNFα.     

Aquaporins and glycerol metabolism

The discovery of aquaporin (AQP) has made a great impact on life sciences. AQPs are a family of homologous water channels widely distributed in plants, unicellular organisms, invertebrates, and vertebrates. So far, 13 AQPs have been identified in human. AQP3, 7, 9, and 10 are subcategorized as aquaglyceroporins which permeabilize glycerol as well as water. Many investigators have demonstrated that AQPs play a crucial role in maintaining water homeostasis, but the physiological significance of some AQPs as a glycerol channel is not fully understood. Adipose tissue is a major source of glycerol and glycerol is one of substrates for gluconeogenesis. This review focuses on recent studies of glycerol metabolism through aquaglyceroporins, and briefly discusses the importance of glycerol channel in adipose tissues and liver.     

Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21

Cardiac metabolism affects systemic energetic balance. Previously, we showed that Krüppel-like factor (KLF)-5 regulates cardiomyocyte PPARα and fatty acid oxidation-related gene expression in diabetes. We surprisingly found that cardiomyocyte-specific KLF5 knockout mice (αMHC-KLF5^?/?) have accelerated diet-induced obesity, associated with increased white adipose tissue (WAT). Alterations in cardiac expression of the mediator complex subunit 13 (Med13) modulates obesity. αMHC-KLF5^?/? mice had reduced cardiac Med13 expression likely because KLF5 upregulates Med13 expression in cardiomyocytes. We then investigated potential mechanisms that mediate cross-talk between cardiomyocytes and WAT. High fat diet-fed αMHC-KLF5^?/? mice had increased levels of cardiac and plasma FGF21, while food intake, activity, plasma leptin, and natriuretic peptides expression were unchanged. Consistent with studies reporting that FGF21 signaling in WAT decreases sumoylation-driven PPARγ inactivation, αMHC-KLF5^?/? mice had less SUMO-PPARγ in WAT. Increased diet-induced obesity found in αMHC-KLF5^?/? mice was absent in αMHC-[KLF5^?/?;FGF21^?/?] double knockout mice, as well as in αMHC-FGF21^?/? mice that we generated. Thus, cardiomyocyte-derived FGF21 is a component of pro-adipogenic crosstalk between heart and WAT.