mRNA In Brown Adipose Tissue Research Articles

Kisspeptin impacts on circadian and ultradian rhythms of core body temperature: Evidence in kisspeptin receptor knockout and kisspeptin knockdown mice

Kisspeptin is vital for the regulation of both fertility and metabolism. Kisspeptin receptor (Kiss1r) knockout (KO) mice exhibit increased adiposity and reduced energy expenditure in adulthood. Kiss1r mRNA is expressed in brown adipose tissue (BAT) and Kiss1r KO mice exhibit reduced Ucp1 mRNA in BAT and impaired thermogenesis. We hypothesised that mice with diminished kisspeptin signalling would exhibit reduced core body temperature (Tc) and altered dynamics of circadian and ultradian rhythms of Tc. Tc was recorded every 15-min over 14-days in gonadectomised wild-type (WT), Kiss1r KO, and also Kiss1-Cre (95% reduction in Kiss1 transcription) mice. Female Kiss1r KOs had higher adiposity and lower Ucp1 mRNA in BAT than WTs. No change was detected in Kiss1-Cre mice. Mean Tc during the dark phase was lower in female Kiss1r KOs versus WTs, but not Kiss1-Cre mice. Female Kiss1r KOs had a lower mesor and amplitude of the circadian rhythm of Tc than did WTs. In WT mice, there were more episodic ultradian events (EUEs) of Tc during the dark phase than the light phase, but this measure was similar between dark and light phases in Kiss1r KO and Kiss1-Cre mice. The amplitude of EUEs was higher in the dark phase in female Kiss1r KO and male Kiss1-Cre mice. Given the lack of clear metabolic phenotype in Kiss1-Cre mice, 5% of Kiss1 transcription may be sufficient for proper metabolic control, as was shown for fertility. Moreover, the observed alterations in Tc suggest that kisspeptin has a role in circadian and ultradian rhythm-driven pathways.

Thermoneutral conditions correct the obese phenotype in female, but not male, Kiss1r knockout mice.

Kisspeptin, a neuropeptide that activates gonadotropin-releasing hormone (GnRH) neurons, has also been implicated as a regulator of energy balance. Kisspeptin receptor (Kiss1r) knockout (KO) mice display an obese phenotype in adulthood compared to wild-type (WT) controls due to reduced energy expenditure. Additionally, experimental evidence shows that the temperature of typical rodent housing conditions (22°C) increases the metabolism of mice above basal levels. Female Kiss1r KO mice show reduced core temperature and impaired temperature adaptation to an acute cold challenge, suggesting their temperature homeostasis processes are altered. The present study examined the phenotype of gonadectomised Kiss1r KO mice at both sub-thermoneutral and thermoneutral temperature (22°C and 30°C). Our results confirmed the obese phenotype in Kiss1r KO mice at 22°C, and revealed a sexually dimorphic effect of thermal neutrality on the phenotype. In female KO mice, the obesity observed at 22°C was attenuated at 30°C. Plasma leptin levels were higher in KO than WT female mice at 22°C (P<0.001) but not at 30°C. Importantly, the expression of Ucp1 mRNA in brown adipose tissue was lower in KO mice compared to WT mice at 22°C (P<0.05), but not different from WT at 30°C. In male KO mice, a metabolic phenotype was observed at 22°C and 30°C. These results provide further evidence for kisspeptin-mediated regulation of adiposity via altered energy expenditure. Moreover, thermoneutral housing alleviated the obese phenotype in female Kiss1r KO mice, compared to WT, indicating the impairment in these mice may relate to an inability to adapt to the chronic cold stress that is experienced at 22°C.

Alterations of the expression levels of CPT-1, SCD1, TRβ-1 and related microRNAs are involved in lipid metabolism impairment in adult rats caused by maternal coconut oil intake during breastfeeding

Abstract We studied the molecular and epigenetic mechanisms associated with dysfunctions caused by postnatal coconut oil exposure. Lactating dams were divided into soybean oil (SO) and coconut oil (CO) groups (0.5 g/kg/gavage). Half of the CO offspring received CO in their chow throughout their lifetime (CO + C). Adult CO offspring had higher liver TRβ-1 mRNA, which is consistent with lower miR-181a and lower DIO2 mRNA in brown adipose tissue (BAT) and higher CPT-1 mRNA in white adipose tissue (WAT). CO + C offspring exhibited higher BAT miR-382*, but DIO2 was unaltered. This group also had higher liver SCD1, miR-122 expression, and WAT SCD1 mRNA. CO and CO + C offspring had lower hepatic CPT-1 mRNA. The disturbances in CO offspring may be partially attributed to alterations in the enzymes involved in lipid metabolism, which may be mediated via mechanisms associated with miR-122. Continuous exposure to CO prohibits some of these changes.

Nesfatin-1 Acts Centrally to Induce Sympathetic Activation of Brown Adipose Tissue and Non-Shivering Thermogenesis.

Nesfatin-1 has originally been established as a bioactive peptide interacting with key hypothalamic nuclei and neural circuitries in control of feeding behavior, while its effect on energy expenditure has only recently been investigated. Hence, the aim of this study was to examine whether centrally acting nesfatin-1 can induce β3-adrenergic stimulation, which is a prerequisite for the activation of thermogenic genes and heat release from interscapular brown adipose tissue, key physiological features that underlie increased energy expenditure. This question was addressed in non-fasted mice stereotactically cannulated to receive nesfatin-1 intracerebroventricularly together with peripheral injection of the β3-adrenoceptor antagonist SR 59230 A, to assess whole-body energy metabolism. Using a minimally invasive thermography technique, we now demonstrate that the thermogenic effect of an anorectic nesfatin-1 dose critically depends on β3 adrenergic stimulation, as the co-administration with SR 59230 A completely abolished heat production from interscapular brown adipose tissue and rise in ocular surface temperature, thus preventing body weight loss. Moreover, through indirect calorimetry it could be shown that the anorectic concentration of nesfatin-1 augments overall caloric expenditure. Plausibly, central administration of nesfatin-1 also enhanced the expression of DIO2 and CIDEA mRNA in brown adipose tissue critically involved in the regulation of thermogenesis.

Photoperiodic changes in adiposity increase sensitivity of female Siberian hamsters to systemic VGF derived peptide TLQP-21.

TLQP-21, a peptide encoded by the highly conserved vgf gene, is expressed in neuroendocrine cells and has been the most prominent VGF-derived peptide studied in relation to control of energy balance. The recent discovery that TLQP-21 is the natural agonist for the complement 3a receptor 1 (C3aR1) has revived interest in this peptide as a potential drug target for obesity. We have investigated its function in Siberian hamsters (Phodopus sungorus), a rodent that displays natural seasonal changes in body weight and adiposity as an adaptation to survive winter. We have previously shown that intracerebroventricular administration of TLQP-21 reduced food intake and body weight in hamsters in their long-day fat state. The aim of our current study was to determine the systemic actions of TLQP-21 on food intake, energy expenditure and body weight, and to establish whether adiposity affected these responses. Peripheral infusion of TLQP-21 (1mg/kg/day for 7 days) in lean hamsters exposed to short photoperiods (SP) reduced cumulative food intake in the home cage (p<0.05), and intake when measured in metabolic cages (P<0.01). Energy expenditure was significantly increased (p<0.001) by TLQP-21 infusion, this was associated with a significant increase in uncoupling protein 1 mRNA in brown adipose tissue (BAT) (p<0.05), and body weight was significantly reduced (p<0.05). These effects of systemic TLQP-21 treatment were not observed in hamsters exposed to long photoperiod (LP) with a fat phenotype. C3aR1 mRNA and protein were abundantly expressed in the hypothalamus, brown and white adipose tissue in hamsters, but changes in expression cannot explain the differential response to TLQP-21 in lean and fat hamsters.

TGF-β1 downregulation in the hypothalamus of obese mice through acute exercise.

Obesity and aging lead to abnormal transforming growth factor-β1 (TGF-β1) signaling in the hypothalamus, triggering the imbalance on glucose metabolism and energy homeostasis. Here, we determine the effect of acute exercise on TGF-β1 expression in the hypothalamus of two models of obesity in mice. The bioinformatics analysis was performed to evaluate the correlation between hypothalamic Tgf-β1 messenger RNA (mRNA) and genes related to thermogenesis in the brown adipose tissue (BAT) by using a large panel of isogenic BXD mice. Thereafter, leptin-deficient (ob/ob) mice and obese C57BL/6 mice fed on a high-fat diet (HFD) were submitted to the acute exercise protocol. Transcriptomic analysis by using BXD mouse reference population database revealed that hypothalamic Tgf-β1 mRNA is negatively correlated with genes related to thermogenesis in brown adipose tissue of BXD mice, such as peroxisome proliferator-activated receptor gamma coactivator and is positively correlated with respiratory exchange ratio. In agreement with these results, leptin-deficient (ob/ob) and HFD-fed mice displayed high levels of Tgf-β1 mRNA in the hypothalamus and reduction of Pgc1α mRNA in BAT. Interestingly, an acute exercise session reduced TGF-β1 expression in the hypothalamus, increased Pgc1α mRNA in the BAT and reduced food consumption in obese mice. Our results demonstrated that acute physical exercise suppressed hypothalamic TGF-β1 expression, increasing Pgc1α mRNA in BAT in obese mice.

Extract of the Microalga Nitzschia laevis Prevents High-Fat-Diet-Induced Obesity in Mice by Modulating the Composition of Gut Microbiota.

The aim of the present study is to investigate the efficacy of Nitzschia laevis extract (NLE) in preventing obesity in mice fed with a high-fat diet (HFD), and the potential underlying mechanisms focusing on modulation of the gut microbiota profile. Physiological, histological, and biochemical parameters and gut microbiota compositions are compared among four experimental groups fed respectively with the following diets for 8 weeks: Normal chow diet, HFD, HFD + low concentration of NLE, and HFD + high concentration of NLE. The results demonstrate that NLE supplementation significantly reduces body weight gain and effectively prevents lipid accumulation in the white adipose tissue and liver of the mice. Mechanistic analysis reveals that NLE promotes the expression of uncoupling protein 1 and peroxisome proliferators-activated receptor-γ coactivator-1 mRNA in brown adipose tissue. Furthermore, NLE protects the gut epithelium and positively reshapes the gut microbiota composition against the damaging effect of HFD. NLE supplementation demonstrates a protective effect against HFD-induced obesity in mice, which is associated with reshaping the profile of gut microbiota. To the best of our knowledge, this has been the first report on the potential of microalgal extract to prevent obesity by modulating gut microbiota.

Nicotinamide riboside induces a thermogenic response in lean mice

AimsNicotinamide Riboside (NR) is a NAD+ booster with wide physiological repercussion including the improvement on glucose and lipid homeostasis, increasing the life expectancy in mammals. However, the effects of NR on metabolism are only partially known. Here, we evaluated the effects of NR on the thermogenic response, highlighting the brown adipose tissue (BAT) in lean mice. Main methodsMale C57BL/67 mice were supplement with NR (400 mg/Kg/day) during 5 weeks. The Comprehensive Lab Animal Monitoring System (CLAMS) and thermographic images were used to evaluated the physiological effects of NR treatment. The BAT were extracted and analyzed by Western Blotting and qPCR. Also, bioinformatics analyses were performed to establish the connection between the NAD+ synthesis pathway in BAT and thermogenic response in several isogenic strains of BXD mice. Key findingsTranscriptomic analysis revealed that genes involved in NAD+ synthesis (Nampt and Nmnat1) in the BAT were negatively correlated with body weight and fat mass. The heat map showed a strong positive correlation between Nampt and Ucp1 mRNA in BAT and body temperature in several strains of BXD lean mice. The experimental approaches demonstrated that oral NR supplementation reduced the abdominal visceral fat depots, with discrete impact on oxygen consumption in C57BL/6J mice. Interestingly, NR significantly increased the body temperature, and this phenomenon was accompanied by high levels of UCP1 protein content and Pgc1α mRNA in BAT. SignificanceThis study demonstrated the oral NR supplementation was sufficient to induce the thermogenic response in lean mice changing the BAT metabolism.

Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice

Excess carbohydrate intake causes obesity in humans. On the other hand, acute administration of fructose, glucose or sucrose in experimental animals has been shown to increase the plasma concentration of anti-obesity hormones such as glucagon-like peptide 1 (GLP-1) and Fibroblast growth factor 21 (FGF21), which contribute to reducing body weight. However, the secretion and action of GLP-1 and FGF21 in mice chronically fed a high-sucrose diet has not been investigated. To address the role of anti-obesity hormones in response to increased sucrose intake, we analyzed mice fed a high-sucrose diet, a high-starch diet or a normal diet for 15 weeks. Mice fed a high-sucrose diet showed resistance to body weight gain, in comparison with mice fed a high-starch diet or control diet, due to increased energy expenditure. Plasma FGF21 levels were highest among the three groups in mice fed a high-sucrose diet, whereas no significant difference in GLP-1 levels was observed. Expression levels of uncoupling protein 1 (UCP-1), FGF receptor 1c (FGFR1c) and β-klotho (KLB) mRNA in brown adipose tissue were significantly increased in high sucrose-fed mice, suggesting increases in FGF21 sensitivity and energy expenditure. Expression of carbohydrate responsive element binding protein (ChREBP) mRNA in liver and brown adipose tissue was also increased in high sucrose-fed mice. These results indicate that FGF21 production in liver and brown adipose tissue is increased in high-sucrose diet and participates in resistance to weight gain.

Defective autophagy causes a maladaptive cardiac phenotype to exercise that leads to premature death and FGF21‐mediated protection against obesity and insulin resistance

Autophagy is induced by exercise in skeletal and cardiac muscle. Skeletal muscle autophagy is required for exercise‐induced metabolic adaptations; yet, impaired skeletal muscle autophagy may cause a compensatory ER stress response that protects against diet‐induced obesity and insulin resistance. The functional importance of cardiac autophagy to the benefits of exercise is uncertain. Here, we generated heart &amp; muscle‐specific Atg7 knockout (Atg7h&amp;mKO) mice to gain further insight into this apparent paradox related to skeletal muscle autophagy and to define the role of cardiac autophagy in exercise‐induced protection against obesity and insulin resistance. Despite exhibiting minimal autophagy in skeletal muscle and heart, Atg7h&amp;mKO mice presented normal exercise capacity and glucose tolerance with a slight reduction in body weight (~5%) at 12–14 weeks of age. After 12 weeks on high‐fat diet (60% calories from fat) sedentary Atg7h&amp;mKO mice gained weight and developed insulin resistance like control littermates (Atg7fl/fl). Exercise (voluntary wheel running) reduced the degree of diet‐induced obesity and glucose intolerance in Atg7h&amp;mKO mice more efficiently; but surprisingly led to premature death of ~40% of these animals. This reduced survival was likely caused by a maladaptive cardiac phenotype as exercise induced physiological cardiac hypertrophy and prevented diet‐induced fibrosis in the hearts of Atg7fl/fl, whereas it exacerbated fibrosis and caused pathological hypertrophy in the hearts of Atg7h&amp;mKO. Interestingly, this maladaptive cardiac phenotype to exercise was accompanied by improved skeletal muscle insulin sensitivity, increased Glut4 mRNA in adipose tissues, and elevated Pgc‐1a and Ucp1 mRNA in brown adipose tissue of Atg7h&amp;mKO suggesting a potential cross‐talk between the heart and peripheral tissues. Analysis of serum indicated a robust increase in circulating FGF21 levels in Atg7h&amp;mKO that exercised, which were accompanied by marked upregulation of Fgf21 mRNA expression exclusively in the heart. Examination of β‐Klotho mRNA, a co‐receptor required for FGF21 signaling, revealed a ~2‐fold upregulation exclusively in white and brown adipose tissues. Our results indicate that autophagy plays a critical role in exercise‐induced protection against cardiac dysfunction in obesity and diabetes. Impaired cardiac autophagy causes a maladaptive phenotype to exercise that leads to premature death, but also potentiates the peripheral metabolic benefits of exercise, at least in part, via a heart‐adipose tissue signaling axis involving FGF21.Support or Funding InformationObesity Research and Education Initiative (OREI) and the Fraternal Order of Eagles Diabetes Research Center (FOEDRC) at the University of Iowa (V.A.L.) and U.S. National Institutes of Health (NIH) grant AR050429 (Z.Y.)

The Peptidic GHS-R antagonist [D-Lys3]GHRP-6 markedly improves adiposity and related metabolic abnormalities in a mouse model of postmenopausal obesity

It was demonstrated that estrogen deficiency and consuming high fat (HF) diet enhanced orexigenic activity of ghrelin. Therefore, we hypothesized that antagonizing of ghrelin action would attenuate food intake and body weight in mice obese both from ovariectomy (OVX) and feeding a HF diet.Ghrelin receptor antagonist [D-Lys3]GHRP-6 after seven days of subcutaneous treatment markedly decreased food intake in OVX mice fed both HF and standard diets; furthermore, it reduced body weight and blood glucose, insulin and leptin, and increased β-hydroxybutyrate level and uncoupling-protein-1 mRNA in brown adipose tissue. Pair-feeding revealed that effect of [D-Lys3]GHRP-6 was primary anorexigenic. Estrogen supplementation reduced anorexigenic effects of [D-Lys3]GHRP-6. OVX [D-Lys3]GHRP-6 treatment in mice on HF diet resulted in markedly increased circulating level and liver expression of a major metabolic regulator, fibroblast growth factor 21.Our data suggest that ghrelin antagonists could be especially beneficial in individuals with common obesity combined with estrogen deficiency.

Quantitative evaluation of the effects of cold exposure of rats on the expression levels of ten FABP isoforms in brown adipose tissue

We quantitatively examined the transcript levels of ten fatty acid-binding protein (FABP) isoforms in the brown adipose tissue (BAT) of rats kept at room temperature and of rats exposed to the cold by Northern blotting using the synthesized RNA of each isoform as an external standard. FABP3-5 were expressed in BAT of both rats maintained at room temperature and those exposed to the cold. FABP4 was the most abundantly expressed isoform, but its transcript level was not significantly affected by cold exposure. FABP3 was slightly expressed in the BAT of rats maintained at room temperature and its transcript level was elevated ten fold by cold exposure. FABP5 was also elevated four fold by cold exposure but the amount of its mRNA in BAT was negligible.

Disturbances in core body temperature in RIP140-null mice

1. RIP140-null mice have reduced core body temperature ( T c), but exhibit normal temperature increase in response to stress, and normal upregulation of UCP1 mRNA in brown adipose tissue (BAT) after β3-AR agonist treatment. 2. Expression levels of some genes key to BAT function are altered in RIP140-null mice, including PGC1α. 3. Newborn RIP140-null mice have reduced BAT mass, altered BAT gene expression and a high death rate. 4. Differences in anxiety behavior and activity also exist in RIP140-null mice. 5. Our observations suggest that RIP140 is involved in a broad range of systems critical to energy balance, thermoregulation, BAT development and behavior.

Induction of fatty acid-binding protein 3 in brown adipose tissue correlates with increased demand for adaptive thermogenesis in rodents

We investigated the contribution of fatty acid-binding protein 3 (FABP3) to adaptive thermogenesis in brown adipose tissue (BAT) in rodents. The expression of FABP3 mRNA in BAT was regulated discriminatively in response to alteration of the ambient temperature, which regulation was similar and reciprocal to the regulation of uncoupling protein 1 (UCP1) and leptin, respectively. FABP3 expression in the BAT was significantly higher in the UCP1-knockout (KO) mice than in the wild-type ones, and these KO mice showed a higher clearance rate of free fatty acid from the plasma. In addition, FABP3 expression in the BAT was increased greatly with the development of diet-induced obesity in mice. These results indicate that the induction of FABP3 in BAT correlates with an increased demand for adaptive thermogenesis in rodents. FABP3 appears to be essential for accelerating fatty acid flux and its oxidation through UCP1 activity for non-shivering thermogenesis in BAT.

Early Undernutrition Leads to Long-Lasting Reductions in Body Weight and Adiposity Whereas Increased Intake Increases Cardiac Fibrosis in Male Rats1,

Previous studies suggest that both overfeeding and undernutrition during development increase the risk of obesity and hypertension in adulthood. In this study, we examined both short- (24 d) and long- (16 wk) term effects of early postnatal over- and underfeeding in rats on body weight, body composition, plasma hormones, adiposity markers, and hypothalamic neuropeptide Y content. Cardiovascular changes were also examined by measuring blood pressure and cardiac fibrosis. Rats raised in litters of 3, 12, or 18 pups per mother were used to model early onset overfeeding, control, and underfeeding, respectively. At 24 d of age, pups raised in small litters (SL) were 10% heavier than pups from normal litters, accompanied by increased organ mass and fat mass, elevated plasma leptin, corticosterone, and uncoupling protein-1 mRNA in brown adipose tissue. On the other hand, pups raised in large litters were 17% lighter with no significant changes in plasma leptin. Overfeeding during the first 3 wk of life led to increased plasma leptin concentration in adulthood, whereas underfed rats remained significantly lighter throughout the study, with no evidence of catch-up growth. Rats raised in SL were more susceptible to developing cardiac fibrosis with a 22% increase in collagen deposition compared with control rats at 16 wk of age (P < 0.05). This was independent of any changes in blood pressure. This study demonstrates that nutritional changes early in postnatal development can have long-lasting effects on body weight, adiposity, and some mediators involved in energy homeostasis and can also lead to structural changes in the heart in adulthood. This highlights the importance of identifying potential early life risk factors involved in the modulation of childhood nutrition.

Antiobesity effects of the β-cell hormone amylin in combination with phentermine or sibutramine in diet-induced obese rats

To characterize the interactive effects of amylin with phentermine or sibutramine on food intake, body weight/composition and gene expression in diet-induced obese (DIO) rats. DIO rats were intraperitoneally injected with a single dose of amylin (10 microg kg(-1)) and/or phentermine (1 mg kg(-1)) or chronically infused with amylin (100 microg kg(-1) d(-1)) or vehicle with or without phentermine (0.5-10 mg kg(-1) d(-1)) or sibutramine (3 mg kg(-1) d(-1)) using two surgically implanted subcutaneous osmotic mini-pumps. Twenty-four hour food intake, locomotor activity and components of meal microstructure (meal size, latency, duration and intermeal interval) were measured following acute administration (amylin, phentermine or amylin+phentermine). Body weight and composition (for amylin and/or sibutramine or phentermine) and metabolism-related gene mRNA expression in the liver (fatty acid synthase, stearoyl-CoA desaturase-1 and carnitine palmitoyltransferase-1) and brown fat (beta-adrenergic receptors and uncoupling protein-1) were measured (for amylin and/or phentermine) after sustained infusion (2 weeks). Acute co-administration of amylin (10 microg kg(-1)) and phentermine (1 mg kg(-1)) reduced acute food intake (up to 19 h) more than either monotherapy. In two studies, sustained subcutaneous infusion of amylin for 2 weeks decreased cumulative food intake (22%) and vehicle-corrected body weight gain ( approximately 4-8%). Phentermine's anorexigenic (10-17%) and weight-reducing effects ( approximately 0-5%) were only evident at the highest dose tested (10 mg kg(-1) d(-1)). Combination of amylin (100 microg kg(-1) d(-1)) and phentermine reduced food intake (30-43%), body weight (8-12%) and adiposity to a greater extent than either monotherapy. Amylin prevented phentermine-induced reductions in UCP-1 mRNA in brown adipose tissue. When amylin+sibutramine were infused, mathematically additive decreases in food intake (up to 45%) and body weight (up to 12%) were evident. Similar to amylin+phentermine treatment, amylin+sibutramine mediated weight loss was attributable to significant reductions in fat mass. Combined treatment of DIO rats with the pancreatic beta-cell hormone amylin and phentermine or sibutramine resulted in additive anorexigenic, weight- and fat-reducing effects.

The Orphan Nuclear Receptor, RORα, Regulates Gene Expression That Controls Lipid Metabolism: STAGGERER (SG/SG) MICE ARE RESISTANT TO DIET-INDUCED OBESITY

Homozygous staggerer mice (sg/sg) display decreased and dysfunctional retinoic acid receptor-related orphan receptor alpha (RORalpha) expression. We observed decreases in serum (and liver) triglycerides and total and high density lipoprotein serum cholesterol in sg/sg mice. Moreover, the sg/sg mice were characterized by reduced adiposity (associated with decreased fat pad mass and adipocyte size). Candidate-based expression profiling demonstrated that the dyslipidemia in sg/sg mice is associated with decreased hepatic expression of SREBP-1c, and the reverse cholesterol transporters, ABCA1 and ABCG1. This is consistent with the reduced serum lipids. The molecular mechanism did not involve aberrant expression of LXR and/or ChREBP. However, ChIP and transfection analyses revealed that RORalpha is recruited to and regulates the activity of the SREBP-1c promoter. Furthermore, the lean phenotype in sg/sg mice is also characterized by significantly increased expression of PGC-1alpha, PGC-1beta, and lipin1 mRNA in liver and white and brown adipose tissue from sg/sg mice. In addition, we observed a significant 4-fold increase in beta(2)-adrenergic receptor mRNA in brown adipose tissue. Finally, dysfunctional RORalpha expression protects against diet-induced obesity. Following a 10-week high fat diet, wild-type but not sg/sg mice exhibited a approximately 20% weight gain, increased hepatic triglycerides, and notable white and brown adipose tissue accumulation. In summary, these changes in gene expression (that modulate lipid homeostasis) in metabolic tissues are involved in decreased adiposity and resistance to diet-induced obesity in the sg/sg mice, despite hyperphagia. In conclusion, we suggest this orphan nuclear receptor is a key modulator of fat accumulation and that selective ROR modulators may have utility in the treatment of obesity.

Increased thermoregulation in cold-exposed transgenic mice overexpressing lipoprotein lipase in skeletal muscle: an avian phenotype?

LPL is an enzyme involved in the breakdown and uptake of lipoprotein triglycerides. In the present study, we examined how the transgenic (Tg) overexpression of human LPL in mouse skeletal muscle affected tolerance to cold temperatures, cold-induced thermogenesis, and fuel utilization during this response. Tg mice and their nontransgenic controls were placed in an environmental chamber and housed in metabolic chambers that monitored oxygen consumption and carbon dioxide production with calorimetry. When exposed to 4 degrees C, an attenuation in the decline in body temperature in Tg mice was accompanied by an increased metabolic rate (15%; P < 0.001) and a reduction in respiratory quotient (P < 0.05). Activity levels, the expression of uncoupling proteins in brown fat and muscle, and lean mass failed to explain the enhanced cold tolerance and thermogenesis in Tg mice. The more oxidative type IIa fibers were favored over the more glycolytic type IIb fibers (P < 0.001) in the gastrocnemius and quadriceps muscles of Tg mice. These data suggest that Tg overexpression of LPL in skeletal muscle increases cold tolerance by enhancing the capacity for fat oxidation, producing an avian-like phenotype in which skeletal muscle contributes significantly to the thermogenic response to cold temperatures.

VGF-Derived Peptide, TLQP-21, Regulates Food Intake and Body Weight in Siberian Hamsters

The Siberian hamster survives winter by decreasing food intake and catabolizing abdominal fat reserves, resulting in a sustained, profound loss of body weight. VGF gene expression is photoperiodically regulated in the hypothalamus with significantly higher expression in lean Siberian hamsters. The aim of this study was to investigate the role of VGF in regulating these seasonal cycles by determining the effects of a VGF-derived peptide (TLQP-21) on food intake and body weight. Acute intracerebroventricular administration of TLQP-21 decreased food intake, and chronic treatment caused a sustained reduction in food intake and body weight and decreased abdominal fat depots. Behavioral analysis revealed that TLQP-21 reduced meal size but not the frequency of feeding bouts, suggesting a primary action on satiety. Hamsters treated with TLQP-21 lost a similar amount of weight as a pair-fed group in which food intake was matched to that of the TLQP-21-treated group. Central or peripheral treatment with TLQP-21 did not produce a significant effect on resting metabolic rate. We conclude that the primary action of TLQP-21 is to decrease food intake rather than increase energy expenditure. TLQP-21 treatment caused a decrease in UCP-1 mRNA in brown adipose tissue, but hypothalamic expression of orexigenic and anorexigenic neuropeptide genes remained unchanged after TLQP-21 treatment, although compensatory increases in NPY and AgRP mRNA were observed in the pair-fed hamsters. The effects of TLQP-21 administration are similar to those in hamsters in short days, suggesting that increased VGF activity may contribute to the hypophagia that underlies the seasonal catabolic state.

Ghrelin affects gastrectomy-induced decrease in UCP1 and β 3-AR mRNA expression in mice

In this study we investigated the effects of gastrectomy (Gx) and of the gastric hormone, ghrelin, on the expression of proteins in brown adipose tissue (BAT) that are thought to be involved in thermogenesis. Heat production in BAT is known to depend upon activation and increased expression of β 3-adrenergic receptors (β 3-AR) and the consequent up-regulation of uncoupling protein 1 (UCP1). Mice were subjected to Gx or sham operation. One week later they started to receive daily subcutaneous injections of either saline or ghrelin (12 nmol) for two or eight weeks. Neither Gx nor ghrelin affected daily food intake. Gx did not lower body weight gain (except during the first post-operative week) but Gx mice responded to eight weeks of ghrelin treatment with a greater body weight increase (37%, p < 0.05) than saline-injected Gx mice; sham-operated mice did not respond to ghrelin. Gx resulted in a greatly reduced expression of both UCP1 and β 3-AR mRNA in BAT (50% reduction or more, p < 0.01) compared to sham-operated mice. Eight weeks of ghrelin treatment raised the UCP1 as well as the β 3-AR mRNA expression in the Gx mice, whereas two weeks of ghrelin treatment decreased UCP1 and β 3-AR mRNA expression compared to Gx mice receiving saline. In fact, mRNA expression in Gx mice after treatment with ghrelin for eight weeks was similar to that in saline-treated sham-operated mice. Ghrelin did not affect UCP1 and β 3-AR mRNA in sham-operated mice neither two nor eight weeks after the operation. The results suggest 1) that signals from the stomach stimulate BAT UCP1 (and possibly thermogenesis) and 2) that ghrelin may contribute to the control of UCP1 expression.