Adaptive Induction of Nonshivering Thermogenesis in Muscle Rather Than Brown Fat Could Counteract Obesity.

Warm-blooded animals such as birds and mammals are able to protect stable body temperature due to various thermogenic mechanisms. These processes can be facultative (occurring only under specific conditions, such as acute cold) and adaptive (adjusting their capacity according to long-term needs). They can represent a substantial part of overall energy expenditure and, therefore, affect energy balance. Classical mechanisms of facultative thermogenesis include shivering of skeletal muscles and (in mammals) non-shivering thermogenesis (NST) in brown adipose tissue (BAT), which depends on uncoupling protein 1 (UCP1). Existence of several alternative thermogenic mechanisms has been suggested. However, their relative contribution to overall heat production and the extent to which they are adaptive and facultative still needs to be better defined. Here we focus on comparison of NST in BAT with thermogenesis in skeletal muscles, including shivering and NST. We present indications that muscle NST may be adaptive but not facultative, unlike UCP1-dependent NST. Due to its slow regulation and low energy efficiency, reflecting in part the anatomical location, induction of muscle NST may counteract development of obesity more effectively than UCP1-dependent thermogenesis in BAT.

Herpesvirus diseases of domestic animals and game species in the Slovak Republic.

Herpesviruses are DNA viruses that cause serious latent infections in humans and animals. These pathogens significantly influence the animal health and economy of animal husbandry. The reduction of production parameters, abortions, birth of weak individuals and by costs associated with the elimination and monitoring of herpesvirus diseases are among the most serious harms caused by herpesviruses. In our review we focused mainly on herpesvirus diseases in pigs and cattle (Aujeszky's disease, bovine infectious pustular vulvovaginitis and balanoposthitis, infectious bovine rhinotracheitis) and herpesvirus diseases in red deer, dogs, and carps. In the past, these herpesvirus diseases have caused considerable economic losses in livestock. At present, several of these diseases are eliminated in the Slovak territory. Currently, a continuous monitoring is carried out not only in populations of domestic animals, but also in wild animals, which are the main reservoirs of the mentioned herpesviruses. Keywords: herpesvirus; Aujeszky's disease; animals; fish; eradication; Slovak Republic.

Mutant Wars2 gene in spontaneously hypertensive rats impairs brown adipose tissue function and predisposes to visceral obesity.

Brown adipose tissue (BAT) plays an important role in lipid and glucose metabolism in rodents and possibly also in humans. Identification of genes responsible for BAT function would shed light on underlying pathophysiological mechanisms of metabolic disturbances. Recent linkage analysis in the BXH/HXB recombinant inbred (RI) strains, derived from Brown Norway (BN) and spontaneously hypertensive rats (SHR), identified two closely linked quantitative trait loci (QTL) associated with glucose oxidation and glucose incorporation into BAT lipids in the vicinity of Wars2 (tryptophanyl tRNA synthetase 2 (mitochondrial)) gene on chromosome 2. The SHR harbors L53F WARS2 protein variant that was associated with reduced angiogenesis and Wars2 thus represents a prominent positional candidate gene. In the current study, we validated this candidate as a quantitative trait gene (QTG) using transgenic rescue experiment. SHR-Wars2 transgenic rats with wild type Wars2 gene when compared to SHR, showed more efficient mitochondrial proteosynthesis and increased mitochondrial respiration, which was associated with increased glucose oxidation and incorporation into BAT lipids, and with reduced weight of visceral fat. Correlation analyses in RI strains showed that increased activity of BAT was associated with amelioration of insulin resistance in muscle and white adipose tissue. In summary, these results demonstrate important role of Wars2 gene in regulating BAT function and consequently lipid and glucose metabolism.

Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype.

This corrects the article DOI: 10.1038/ijo.2016.228.

Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype.

BACKGROUND/OBJECTIVE: Futile substrate cycling based on lipolytic release of fatty acids (FA) from intracellular triacylglycerols (TAG) and their re-esterification (TAG/FA cycling), as well as de novo FA synthesis (de novo lipogenesis (DNL)), represent the core energy-consuming biochemical activities of white adipose tissue (WAT). We aimed to characterize their roles in cold-induced thermogenesis and energy homeostasis. METHODS: Male obesity-resistant A/J and obesity-prone C57BL/6J mice maintained at 30 °C were exposed to 6 °C for 2 or 7 days. In epididymal WAT (eWAT), TAG synthesis and DNL were determined using in vivo 2H incorporation from 2H2O into tissue TAG and nuclear magnetic resonance spectroscopy. Quantitative real-time-PCR and/or immunohistochemistry and western blotting were used to determine the expression of selected genes and proteins in WAT and liver. RESULTS: The mass of WAT depots declined during cold exposure (CE). Plasma levels of TAG and non-esterified FA were decreased by day 2 but tended to normalize by day 7 of CE. TAG synthesis (reflecting TAG/FA cycle activity) gradually increased during CE. DNL decreased by day 2 of CE but increased several fold over the control values by day 7. Expression of genes involved in lipolysis, glyceroneogenesis, FA re-esterification, FA oxidation and mitochondrial biogenesis in eWAT was induced during CE. All these changes were more pronounced in obesity-resistant A/J than in B6 mice and occurred in the absence of uncoupling protein 1 in eWAT. Expression of markers of glyceroneogenesis in eWAT correlated negatively with hepatic FA synthesis by day 7 in both strains. Leptin and fibroblast growth factor 21 plasma levels were differentially affected by CE in the two mouse strains. CONCLUSIONS: Our results indicate integrated involvement of (i) TAG/FA cycling and DNL in WAT, and (ii) hepatic very-low-density lipoprotein-TAG synthesis in the control of blood lipid levels and provision of FA fuels for thermogenesis in cold. They suggest that lipogenesis in WAT contributes to a lean phenotype.

Enhancement of brown fat thermogenesis using chenodeoxycholic acid in mice.

OBJECTIVE: Besides their role in lipid absorption, bile acids (BAs) can act as signalling molecules. Cholic acid was shown to counteract obesity and associated metabolic disorders in high-fat-diet (cHF)-fed mice while enhancing energy expenditure through induction of mitochondrial uncoupling protein 1 (UCP1) and activation of non-shivering thermogenesis in brown adipose tissue (BAT). In this study, the effects of another natural BA, chenodeoxycholic acid (CDCA), on dietary obesity, UCP1 in both interscapular BAT and in white adipose tissue (brite cells in WAT), were characterized in dietary-obese mice. RESEARCH DESIGN: To induce obesity and associated metabolic disorders, male 2-month-old C57BL/6J mice were fed cHF (35% lipid wt wt(-1), mainly corn oil) for 4 months. Mice were then fed either (i) for 8 weeks with cHF or with cHF with two different doses (0.5%, 1%; wt wt(-1)) of CDCA (8-week reversion); or (ii) for 3 weeks with cHF or with cHF with 1% CDCA, or pair-fed (PF) to match calorie intake of the CDCA mice fed ad libitum; mice on standard chow diet were also used (3-week reversion). RESULTS: In the 8-week reversion, the CDCA intervention resulted in a dose-dependent reduction of obesity, dyslipidaemia and glucose intolerance, which could be largely explained by a transient decrease in food intake. The 3-week reversion revealed mild CDCA-dependent and food intake-independent induction of UCP1-mediated thermogenesis in interscapular BAT, negligible increase of UCP1 in subcutaneous WAT and a shift from carbohydrate to lipid oxidation. CONCLUSIONS: CDCA could reverse obesity in cHF-fed mice, mainly in response to the reduction in food intake, an effect probably occuring but neglected in previous studies using cholic acid. Nevertheless, CDCA-dependent and food intake-independent induction of UCP1 in BAT (but not in WAT) could contribute to the reduction in adiposity and to the stabilization of the lean phenotype.

Sex differences during the course of diet-induced obesity in mice: adipose tissue expandability and glycemic control.

OBJECTIVE: Adverse effects of obesity on glucose homeostasis are linked to low-grade adipose tissue inflammation and accumulation of lipids in non-adipose tissues. The goal of this study was to evaluate the role of adipose tissue plasticity in a less severe deterioration of glucose homeostasis in females compared with males during the course of high-fat (HF) feeding in mice. DESIGN: Mice of the C57BL/6N strain were fed either a chow or obesogenic HF diet for up to 35 weeks after weaning. Metabolic markers and hormones in plasma, glucose homeostasis, adipocyte size and inflammatory status of gonadal (gWAT) and subcutaneous (scWAT) adipose depots and liver steatosis were evaluated at 15 and 35 weeks of HF feeding. RESULTS: HF-fed males were heavier than females until week ∼20, after which the body weights stabilized at a similar level (55-58 g) in both sexes. Greater weight gain and fat accumulation in females were associated with larger adipocytes in gWAT and scWAT at week 35. Although adipose tissue macrophage infiltration was in general less frequent in scWAT, it was reduced in both fat depots of female as compared with male mice; however, the expression of inflammatory markers in gWAT was similar in both sexes at week 35. In females, later onset of the impairment of glucose homeostasis and better insulin sensitivity were associated with higher plasma levels of adiponectin (weeks 0, 15 and 35) and reduced hepatosteatosis (weeks 15 and 35). CONCLUSIONS: Compared with males, female mice demonstrate increased capacity for adipocyte enlargement in response to a long-term HF feeding, which is associated with reduced adipose tissue macrophage infiltration and lower fat deposition in the liver, and with better insulin sensitivity. Our data suggest that adipose tissue expandability linked to adiponectin secretion might have a role in the sex differences observed in obesity-associated metabolic disorders.

Role of energy charge and AMP-activated protein kinase in adipocytes in the control of body fat stores.

As indicated by in vitro studies, both lipogenesis and lipolysis in adipocytes depend on the cellular ATP levels. Ectopic expression of mitochondrial uncoupling protein 1 (UCP1) in the white adipose tissue of the aP2-Ucp1 transgenic mice reduced obesity induced by genetic or dietary manipulations. Furthermore, respiratory uncoupling lowered the cellular energy charge in adipocytes, while the synthesis of fatty acids (FA) was inhibited and their oxidation increased. Importantly, the complex metabolic changes triggered by ectopic UCP1 were associated with the activation of AMP-activated protein kinase (AMPK), a metabolic master switch, in adipocytes. Effects of several typical treatments that reduce adiposity, such as administration of leptin, beta-adrenoceptor agonists, bezafibrate, dietary n-3 polyunsaturated FA or fasting, can be compared with a phenotype of the aP2-Ucp1 mice. These situations generally lead to the upregulation of mitochondrial UCPs and suppression of the cellular energy charge and FA synthesis in adipocytes. On the other hand, FA oxidation is increased. Moreover, it has been shown that AMPK in adipocytes can be activated by adipocyte-derived hormones leptin and adiponectin, and also by insulin-sensitizes thiazolidinediones. Thus, it is evident that metabolism of adipose tissue itself is important for the control of body fat content and that the cellular energy charge and AMPK are involved in the control of lipid metabolism in adipocytes. The reciprocal link between synthesis and oxidation of FA in adipocytes represents a prospective target for the new treatment strategies aimed at reducing obesity.

Energy metabolism of adipose tissue--physiological aspects and target in obesity treatment.

Body fat content is controlled, at least in part, by energy charge of adipocytes. In vitro studies indicated that lipogenesis as well as lipolysis depend on cellular ATP levels. Respiratory uncoupling may, through the depression of ATP synthesis, control lipid metabolism of adipose cells. Expression of some uncoupling proteins (UCP2 and UCP5) as well as other protonophoric transporters can be detected in the adipose tissue. Expression of other UCPs (UCP1 and UCP3) can be induced by pharmacological treatments that reduce adiposity. A negative correlation between the accumulation of fat and the expression of UCP2 in adipocytes was also found. Ectopic expression of UCP1 in the white fat of aP2-Ucp1 transgenic mice mitigated obesity induced by genetic or dietary factors. In these mice, changes in lipid metabolism of adipocytes were associated with the depression of intracellular energy charge. Recent data show that AMP-activated protein kinase may be involved in the complex changes elicited by respiratory uncoupling in adipocytes. Changes in energy metabolism of adipose tissue may mediate effects of treatments directed against adiposity, dyslipidemia, and insulin resistance.

Mitochondrial uncoupling and lipid metabolism in adipocytes.

Metabolism of white adipose tissue is involved in the control of body fat content. In vitro experiments indicated a dependence of lipogenesis on mitochondrial ATP production, as well as a reciprocal link between hormonal effects on metabolism and energetics of adipocytes. Therefore, mitochondrial uncoupling in adipocytes that results in stimulation of energy dissipation and depression of ATP synthesis may contribute to control of lipid metabolism and adiposity. This is supported by the expression of protonophoric proteins in adipocytes, e.g. uncoupling proteins (UCPs) 2 and 5, and some anion transporters, and induction of UCP1 and UCP3 in white fat by pharmacological treatments that reduce adiposity. Negative correlation between expression of UCPs in adipocytes and accumulation of white fat was also found. Expression of UCP1 from the adipose-specific promoter in aP2-Ucp1 transgenic mice mitigated obesity induced by genetic or dietary factors. The obesity resistance, accompanied by mitochondrial uncoupling in adipocytes and increased energy expenditure, resulted from ectopic expression of UCP1 in white but not in brown fat. Probably due to depression of ATP/ADP ratio in white fat of transgenic mice, both fatty acid synthesis and lipolytic action of noradrenaline in adipocytes were relatively low. These results support the role of protonophoric proteins in adipocytes in the control of adiposity. The main function of these proteins in white fat may be modulation of lipogenesis and intracellular hormone signalling. Augmentation of energy expenditure may be of relatively small importance, in accordance with the low oxidative capacity of white adipocytes.