Brown fat thermogenesis and body weight regulation in mice: relevance to humans

Physiological, pharmacological and genetic studies in dogs, mice and rats have established that the uncoupling protein-1 (UCP1)-based brown adipose tissue system has an important role in the regulation of body temperature. Although it may be possible to create laboratory conditions in which mice with inactivated Ucp1 can survive in a modestly cooled environment, data overwhelmingly support the conclusion that the UCP1/BAT system has evolved to maintain body temperature at 37?°C. The corollary to this conclusion is that any influence UCP1/BAT might have on body weight regulation is a secondary function. The idea that BAT prevents obesity by burning off excess energy to maintain energy balance seems incompatible with evolutionary biology. Premodern humans spent an enormous amount of energy either running to catch their meal or avoiding becoming a meal themselves; consequently, there was no obesity. Nevertheless, although secondary to body temperature regulation, UCP1/BAT is extraordinarily effective at reducing adiposity and insulin resistance in mice and rats. Variation among mice in susceptibility to diet-induced obesity is correlated with the induction of brown adipocytes in traditional white fat depots (wBAT). Both genetic and cell biology-based experimentation have shown that the cellular origins of wBAT are different from those of interscapular-like brown adipocytes (iBAT). Do they have different functions? We have analyzed the effects of the early nutritional environment on the induction of brown adipocytes in inguinal fat to test the hypothesis that wBAT is primarily involved in body weight regulation. Although undernutrition during lactation severely suppresses wBAT at 21 days of age, undernourished mice fed a normal chow diet ad libitum at weaning recovered their normal wBAT and iBAT systems as young adults. The function of wBAT does not seem to be uniquely devoted to body weight regulation.     

Corticotropin-releasing hormone-mediated pathway of leptin to regulate feeding,adiposity, and uncoupling protein expression in mice

To examine the functional role of CRH in the regulation of energy homeostasis by leptin, we measured the effects of the CRH antagonist, alpha-helical CRH 8-41 (alphaCRH) on a number of factors affected by leptin activity. These included food intake, body weight, hypothalamic c-fos-like immunoreactivity (c-FLI), weight and histological characterization of white adipose tissue, and mRNA expressions of uncoupling protein (UCP) in brown adipose tissue (BAT) in C57Bl/6 mice. Central infusion of leptin into the lateral cerebroventricle (icv) caused significant induction of c-FLI in the paraventricular nucleus (PVN), ventromedial hypothalamic nucleus (VMH), dorsomedial hypothalamic nucleus, and arcuate nucleus. In all these nuclei, the effect of leptin on expression of cFLI in the PVN and VMH was decreased by treatment with alphaCRH. Administration of leptin markedly decreased cumulative food intake and body weight with this effect being attenuated by pretreatment with alphaCRH. In peripheral tissue, leptin up-regulated BAT UCP1 mRNA expression and reduced fat depositions in this tissue. Those changes in BAT were also decreased by treatment with alphaCRH. As a consequence of the effects on food intake or energy expenditure, treatment with alphaCRH attenuated the leptin-induced reduction of body adiposity, fat cell size, triglyceride contents, and ob mRNA expression in white adipose tissue. Taken together, these results indicate that CRH neurons in the PVN and VMH may be an important mediator for leptin that contribute to regulation of feeding, adiposity, and UCP expression.     

Norepinephrine is required for leptin effects on gene expression in brown and white adipose tissue.

Exogenous leptin enhances energy utilization in ob/ob mice by binding its hypothalamic receptor and selectively increasing peripheral fat oxidation. Leptin also increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), but the neurotransmitter that mediates this effect has not been established. The present experiments sought to determine whether leptin regulates UCP1 expression in BAT and its own expression in white adipose tissue (WAT) through the long or short forms of leptin receptor and modulation of norepinephrine release. Mice lacking dopamine beta-hydroxylase (Dbh-/-), the enzyme responsible for synthesizing norepinephrine and epinephrine from dopamine, were treated with leptin (20 microg/g body weight/day) for 3 days before they were euthanized. UCP1 messenger RNA (mRNA) and protein expression were 5-fold higher in BAT from control (Dbh+/-) compared with Dbh-/- mice. Leptin produced a 4-fold increase in UCP1 mRNA levels in Dbh+/- mice but had no effect on UCP1 expression in Dbh-/-. The beta3-adrenergic agonist, CL-316,243 increased UCP1 expression and established that BAT from both groups of mice was capable of responding to beta-adrenergic stimulation. Similarly, exogenous leptin reduced leptin mRNA in WAT from Dbh+/- but not Dbh-/- mice. In separate experiments, leptin produced comparable reductions in food intake in both Dbh+/- and Dbh-/- mice, illustrating that norepinephrine is not required for leptin's effect on food intake. Lastly, db/db mice lacking the long form of the leptin receptor failed to increase UCP1 mRNA in response to exogenous leptin but increased UCP1 mRNA in response to CL-316,243. These studies establish that norepinephrine is required for leptin to regulate its own expression in WAT and UCP1 expression in BAT and indicate that these effects are likely mediated through the centrally expressed long form of the leptin receptor.     

Leptin-deficient mice backcrossed to the BALB/cJ genetic background have reduced adiposity, enhanced fertility, normal body temperature, and severe diabetes.

A deficiency of leptin synthesis in mice results in a complex phenotype characterized by morbid obesity, diabetes, sterility, and defective thermogenesis. To determine whether the genetic background could alter the pleiotropic effects of leptin deficiency, we backcrossed the ob mutation for 10 generations from the C57BL/6J to the BALB/cJ genetic background. Compared with C57BL/6J ob/ob mice, BALB/cJ ob/ob mice showed at 27 wk of age a 35-40% reduction in body weight attributed to a 60% decrease in white adipose tissue mass. Food intake was not significantly different between the two obese strains, suggesting distinct utilization of energy intake. In the fed state, BALB/cJ ob/ob mice had elevated insulin and triglycerides levels, demonstrating a worsening effect on diabetes. At the reproductive level and in contrast to sterile C57BL/6J ob/ob mice, male and female BALB/cJ ob/ob mice were capable of reproducing after a mating period of 16 and 32 wk, respectively. At thermoneutrality, the body temperature of BALB/cJ ob/ob mice was 2.9 C higher than that of C57BL/6J ob/ob mice, whereas exposure of both groups to 4 C demonstrated a prolonged cold tolerance of BALB/cJ ob/ob mice. These studies show that the abnormalities caused by leptin deficiency can be genetically dissected and separated from each other, suggesting discrete pathways controlled by leptin modifier genes.     

Peroxisome proliferator-activated receptor gamma agonism increases the capacity for sympathetically mediated thermogenesis in lean and ob/ob mice

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma modulates the expression of numerous genes involved in glucose and lipid homeostasis and plays a critical role in adipocyte differentiation. Expression of uncoupling protein (UCP)1, which is necessary for thermogenesis, is strongly stimulated by PPARgamma agonists but without an increase in energy expenditure. This study was designed to assess whether PPARgamma-induced UCP1 has any functional impact and, if so, whether it involves sympathetic activity. In a first phase, obese ob/ob C57BL/6J mice and lean controls were treated for 2 wk with the PPARgamma agonist [2-(2-[4-phenoxy-2-propylphenoxy]ethyl)indole-5-acetic acid] (COOH). COOH induced UCP1 expression in brown and white adipose tissues as well as that of other genes associated with substrate oxidation and thermogenesis. However, UCP1 induction did not increase energy expenditure, as assessed by indirect calorimetry and other energy balance measurements. In a second phase, mice received for an additional 2 wk a combination of COOH and the beta(3)-adrenergic receptor (beta(3)-AR) agonist CL-316243 to stimulate the adrenergic signaling pathway and assess whether COOH-induced UCP1 was physiologically functional. The beta(3)-AR agonist stimulated thermogenesis in lean and ob/ob mice, an effect that was much stronger in COOH-pretreated mice, which exhibited lower respiratory quotient, higher oxygen consumption, and marked weight and fat mass loss, compared with mice not pretreated with COOH. These results demonstrate that PPARgamma agonism increases the thermogenic potential of white and brown adipose depots in lean and obese mice. This enhanced capacity leads to increased thermogenesis under beta-adrenergic stimulation, suggesting that the sympathetic drive is blunted by PPARgamma agonism.     

Deficiency of PTP1B in Leptin Receptor-Expressing Neurons Leads to Decreased Body Weight and Adiposity in Mice

Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed tyrosine phosphatase implicated in the negative regulation of leptin and insulin receptor signaling. PTP1B(-/-) mice possess a lean metabolic phenotype attributed at least partially to improved hypothalamic leptin sensitivity. Interestingly, mice lacking both leptin and PTP1B (ob/ob:PTP1B(-/-)) have reduced body weight compared with mice lacking leptin only, suggesting that PTP1B may have important leptin-independent metabolic effects. We generated mice with PTP1B deficiency specifically in leptin receptor (LepRb)-expressing neurons (LepRb-PTP1B(-/-)) and compared them with LepRb-Cre-only wild-type (WT) controls and global PTP1B(-/-) mice. Consistent with PTP1B's role as a negative regulator of leptin signaling, our results show that LepRb-PTP1B(-/-) mice are leptin hypersensitive and have significantly reduced body weight when maintained on chow or high-fat diet (HFD) compared with WT controls. LepRb-PTP1B(-/-) mice have a significant decrease in adiposity on HFD compared with controls. Notably, the extent of attenuated body weight gain on HFD, as well as the extent of leptin hypersensitivity, is similar between LepRb-PTP1B(-/-) mice and global PTP1B(-/-) mice. Overall, these results demonstrate that PTP1B deficiency in LepRb-expressing neurons results in reduced body weight and adiposity compared with WT controls and likely underlies the improved metabolic phenotype of global and brain-specific PTP1B-deficient models. Subtle phenotypic differences between LepRb-PTP1B(-/-) and global PTP1B(-/-) mice, however, suggest that PTP1B independent of leptin signaling may also contribute to energy balance in mice.     

Apelin, an APJ receptor ligand, regulates body adiposity and favors the messenger ribonucleic acid expression of uncoupling proteins in mice

Apelin, the endogenous ligand of the APJ receptor, has been identified in a variety of tissues, including stomach, heart, skeletal muscle, and white adipose tissue. We sought to clarify the effects of apelin on body adiposity and the expression of uncoupling proteins (UCPs) in C57BL/6 mice. Treatment with ip apelin at a dose of 0.1 mumol/kg.d for 14 d decreased the weight of white adipose tissue and serum levels of insulin and triglycerides, compared with controls, without influencing food intake. Apelin treatment also decreased body adiposity and serum levels of insulin and triglycerides in obese mice fed a high-fat diet. Apelin increased the serum adiponectin level and decreased that of leptin. Additionally, apelin treatment increased mRNA expression of UCP1, a marker of peripheral energy expenditure, in brown adipose tissue (BAT) and of UCP3, a regulator of fatty acid export, in skeletal muscle. In addition, immunoblot bands and relative densities of UCP1 content in BAT were also higher in the apelin group than controls. Furthermore, apelin treatment increased body temperature and O(2) consumption and decreased the respiratory quotient. In conclusion, apelin appears to regulate adiposity and lipid metabolism in both lean and obese mice. In addition, apelin regulates insulin resistance by influencing the circulating adiponectin level, the expression of BAT UCP1, and energy expenditure in mice.     

Torpor in mice is induced by both leptin-dependent and -independent mechanisms

We tested the effect of chronic leptin treatment on fasting-induced torpor in leptin-deficient A-ZIP/F-1 and ob/ob mice. A-ZIP/F-1 mice have virtually no white adipose tissue and low leptin levels, whereas ob/ob mice have an abundance of fat but no leptin. These two models allowed us to examine the roles of adipose tissue and leptin in the regulation of entry into torpor. Torpor is a short-term hibernation-like state that allows conservation of metabolic fuels. We first characterized the A-ZIP/F-1 animals, which have a 10-fold reduction in total body triglyceride stores. Upon fasting, A-ZIP/F-1 mice develop a lower metabolic rate and decreased plasma glucose, insulin, and triglyceride levels, with no increase in free fatty acids or beta-hydroxybutyrate. Unlike control mice, by 24 hr of fasting, they have nearly exhausted their triglycerides and are catabolizing protein. To conserve energy supplies during fasting, A-ZIP/F-1 (but not control) mice entered deep torpor, with a minimum core body temperature of 24 degrees C, 2 degrees C above ambient. In ob/ob mice, fasting-induced torpor was completely reversed by leptin treatment. In contrast, neither leptin nor thyroid hormone prevented torpor in A-ZIP/F-1 mice. These data suggest that there are at least two signals for entry into torpor in mice, a low leptin level and another signal that is independent of leptin and thyroid hormone levels. Studying rodent torpor provides insight into human torpor-like states such as near drowning in cold water and induced hypothermia for surgery.     

Role of leptin in peroxisome proliferator-activated receptor gamma coactivator-1 expression

Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1), a cold-induced protein expressed in brown adipose tissue (BAT), plays a role in adaptive thermogenesis by up-regulating uncoupling proteins (UCP). Here, we explore its relationship to the thermogenic actions of leptin, which also up-regulates UCPs. We find that PGC-1 messenger RNA (mRNA) is markedly reduced in BAT of obese leptin-deficient (ob/ob mice) and leptin-unresponsive (db/db mice and Zucker diabetic fatty fa/fa rats) rodents. Whereas, after cold exposure (6 C for 7 h), PGC-1 mRNA increases 2.6-fold in BAT of lean +/+ rats, it rises only 30% in fa/fa rats. Four days after induction of hyperleptinemia (>30 ng/ml) in Wistar rats, by adenovirus gene transfer, PGC-1 mRNA in BAT was 2.3-fold and UCP-1, 4-fold above controls. In isolated white adipocytes, PGC-1 mRNA increased 4.4-fold within 6 h of incubation with 20 ng/ml of leptin. We conclude that leptin action is required for normal basal and cold-stimulated PGC-1 expression in BAT in rodents and that hyperleptinemia rapidly up-regulates its expression, at least in part, by direct action.     

Evidence for a compensated thermogenic defect in transgenic mice lacking the mitochondrial glycerol-3-phosphate dehydrogenase gene

A role for mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) in thermogenesis was investigated in transgenic mice lacking the mGPD gene (mGPD-/-). Reared and studied at 22 C, these mice have a small, but significant, reduction (7-10%) in energy expenditure, as evidenced by oxygen consumption (QO2) and food intake, and show signs of increased brown adipose tissue (BAT) stimulation, higher plasma T4 and T3 concentrations, as well as increased uncoupling protein 3 (UCP3) expression in muscle. When acclimated at thermoneutrality temperature (32 C), QO2 decreased in both genotypes, but the difference between them widened to 16%, whereas BAT underwent atrophy, and plasma T4 and T3 levels and UCP3 mRNA decreased, yet T3 and UCP3 persisted at significantly higher levels in mGPD-/- mice. Such differences disappeared when the mice were rendered hypothyroid. A compensatory role for the observed changes in BAT, thyroid hormone levels, and UCP3 was investigated with a 2-h cold challenge of 12 C in euthyroid and hypothyroid mice. No hypothermia ensued if the mice had been acclimated at 22 C, but when acclimated at 32 C, euthyroid mGPD-/- mice became significantly more hypothermic than the wild-type controls. When rendered hypothyroid, this difference was accentuated, and the mGPD-/- mice developed profound hypothermia ( approximately 28 vs. 34 C in wild-type mice; P < 0.001). Thus, mGPD-deficient mice have, despite increased plasma T4 and T3, a small, but distinct, reduction in obligatory thermogenesis, which is compensated by increased BAT facultative thermogenesis and by thyroid hormone-dependent mechanisms using other proteins, possibly UCP3. The results support a role for mGPD in thyroid hormone thermogenesis.     

Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice

Aims/hypothesis

Adiponectin is an adipocyte-derived hormone that plays an important role in energy homeostasis. The main objective of this study was to investigate whether or not adiponectin regulates brown adipose tissue (BAT) activation and thermogenesis.

Methods

Core body temperatures (CBTs) of genetic mouse models were monitored at room temperature and during cold exposure. Cultured brown adipocytes and viral vector-mediated gene transduction were used to study the regulatory effects of adiponectin on Ucp1 gene expression and the underlying mechanisms.

Results

The CBTs of adiponectin knockout mice (Adipoq ^?/?) were significantly higher than those of wild type (WT) mice both at room temperature and during the cold (4°C) challenge. Conversely, reconstitution of adiponectin in Adipoq ^?/? mice significantly blunted β adrenergic receptor agonist-induced thermogenesis of interscapular BAT. After 10 days of intermittent cold exposure, Adipoq ^?/? mice exhibited higher UCP1 expression and more brown-like structure in inguinal fat than WT mice. Paradoxically, we found that the anti-thermogenic effect of adiponectin requires neither AdipoR1 nor AdipoR2, two well-known adiponectin receptors. In sharp contrast to the anti-thermogenic effects of adiponectin, AdipoR1 and especially AdipoR2 promote BAT activation. Mechanistically, adiponectin was found to inhibit Ucp1 gene expression by suppressing β₃-adrenergic receptor expression in brown adipocytes.

Conclusions/interpretation

This study demonstrates that adiponectin suppresses thermogenesis, which is likely to be a mechanism whereby adiponectin reduces energy expenditure.     

Obesity-related fatty liver is unchanged in mice deficient for mitochondrial uncoupling protein 2

Nonalcoholic fatty liver disease (NAFLD), a prevalent condition associated with obesity, has the potential of evolving into end-stage liver disease. The biochemical mechanisms that define the progression of NAFLD are not well known, but reactive oxygen species (ROS) have been implicated in this process. Uncoupling protein (UCP) 2 is a mitochondrial inner-membrane protein that mediates proton leak, uncouples adenosine triphosphate (ATP) synthesis, and negatively regulates ROS production. UCP2 expression is increased in various animal models of NAFLD. Up-regulation of UCP2 may compromise cellular ATP levels and worsen liver damage, or it may be protective by ROS reduction in NAFLD. This study aimed to obtain a definitive answer as to whether increased UCP2 expression contributes to NAFLD. UCP2-/- mice were exposed to obesity by crossbreeding with ob/ob mice and by long-term high-fat feeding to study the effect of UCP2 deficiency on the outcome of NAFLD. Steatohepatitis score of crossbred mice (ob/ob/ko) was similar to that of ob/ob mice at 25 weeks. No compensatory increase was observed in the expression of UCP5 in ob/ob/ko livers. To unmask the effects of absent leptin and its potential proinflammatory actions, steatosis was also induced in UCP2-/- mice by a high-fat diet continued for 6 months. Serum alanine aminotransferase (ALT) levels remained normal, and the steatohepatitis score in UCP2-/- mice was the same as in wild-type controls. We conclude that increased expression of UCP2 in the livers of mice with genetically or diet-induced obesity exerts neither protective nor deleterious effects on the severity of fatty liver disease.     

Double leptin and melanocortin-4 receptor gene mutations have an additive effect on fat mass and are associated with reduced effects of leptin on weight loss and food intake

Melanocortin-4 receptors (MC4Rs) are involved in the regulation of food intake, sympathetic nervous activity, and adrenal and thyroid function by leptin. The role of MC4Rs in regulating energy balance by leptin was investigated using double heterozygote or homozygous leptin (Lep(ob)) and Mc4r gene mutant mice. Double heterozygous or homozygous mutants were generated by crossing MC4R knockout (Mc4r-/-) mice, backcrossed onto C57BL/6J, with B6.V-Lep(ob) mice. Energy expenditure was measured using indirect calorimetry. The effect of leptin on food intake, weight loss, insulin, and corticosterone was compared for Lep(ob)/Lep(ob)Mc4r-/- mice and Lep(ob)/Lep(ob) mice. Double heterozygous and homozygous mutants exhibited an additive effect on fat mass. The 2-fold increase in body weight associated with severe obesity of Lep(ob)/Lep(ob) mice was associated with a significantly higher 24 h total and resting energy expenditure. The effect of obesity on energy expenditure was attenuated by 50% in Lep(ob)/Lep(ob) Mc4r+/- and Lep(ob)/Lep(ob) Mc4r-/- mice. Loss of MC4Rs did not affect basal food intake of Lep(ob)/Lep(ob) mice but was associated with partial leptin resistance in terms of food intake and weight loss. Leptin suppression of insulin and corticosterone in Lep(ob)/Lep(ob) mice were not significantly affected by Mc4r genotype. These results suggest a complex interaction between the Lep and Mc4r genes in energy homeostasis and suggest that MC4Rs retain significant anti-obesity function in the obese leptin-deficient state. Increased adiposity with double mutations may involve a reduction in energy expenditure. MC4Rs might have a modest role in the regulation of energy balance by exogenously administered leptin, primarily effecting food intake.     

Uncoupling protein 2 negatively regulates glucose-induced glucagon-like peptide 1 secretion

It is known that endogenous levels of the incretin hormone glucagon-like peptide 1 (GLP1) can be enhanced by various secretagogues, but the mechanism underlying GLP1 secretion is still not fully understood. We assessed the possible effect of uncoupling protein 2 (UCP2) on GLP1 secretion in mouse intestinal tract and NCI-H716 cells, a well-characterized human enteroendocrine L cell model. Localization of UCP2 and GLP1 in the gastrointestinal tract was assessed by immunofluorescence staining. Ucp2 mRNA levels in gut were analyzed by quantitative RT-PCR. Human NCI-H716 cells were transiently transfected with siRNAs targeting UCP2. The plasma and ileum tissue levels of GLP1 (7-36) amide were measured using an ELISA kit. UCP2 was primarily expressed in the mucosal layer and colocalized with GLP1 in gastrointestinal mucosa. L cells secreting GLP1 also expressed UCP2. After glucose administration, UCP2-deficient mice showed increased glucose-induced GLP1 secretion compared with wild-type littermates. GLP1 secretion increased after NCI-H716 cells were transfected with siRNAs targeting UCP2. UCP2 was markedly upregulated in ileum tissue from ob/ob mice, and GLP1 secretion decreased compared with normal mice. Furthermore, GLP1 secretion increased after administration of genipin by oral gavage. Taken together, these results reveal an inhibitory role of UCP2 in glucose-induced GLP1 secretion.     

Is leptin a key factor which develops obesity by ovariectomy?

Withdrawal of estrogen by ovariectomy increases adiposity, but decreases the circulating levels of the ob gene product, leptin, which inhibits food intake. The reduction of circulating leptin levels may thus play an important role in the induction of obesity by ovariectomy. To examine this hypothesis, body weight change by ovariectomy was investigated in leptin-deficient genetically obese (ob/ob) mice with leptin supplement. Prior to the operation, obese (ob/ob) female mice were treated with intraperitoneal administration of recombinant mouse leptin (1.0 microg/g body weight/day) for 8 days. Then, half of the leptin-treated mice and their lean littermates were bilaterally ovariectomized and their body weight changes were observed for 56 days. From 16 days after the operation, a significant increase in body weight by ovariectomy was observed only in lean mice without leptin treatment. From 44 days, a significant body weight gain by ovariectomy was observed in leptin-treated obese mice. Ovariectomy significantly increased retroperitoneal white adipose tissue weight in their lean littermates, but not in leptin-treated obese mice. It was suggested that the reduction of circulating leptin levels may play an important role in the increases of acute phase body weight gain by ovariectomy, but during static phase, the direct effects of estrogen withdrawal may appear independent of leptin-mediated effects.     

Role of uncoupling protein UCP2 in cell-mediated immunity: how macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes

Infiltration of inflammatory cells into pancreatic islets of Langerhans and selective destruction of insulin-secreting beta-cells are characteristics of type 1 diabetes. Uncoupling protein 2 (UCP2) is a mitochondrial protein expressed in immune cells. UCP2 controls macrophage activation by modulating the production of mitochondrial reactive oxygen species (ROS) and MAPK signaling. We investigated the role of UCP2 on immune cell activity in type 1 diabetes in Ucp2-deficient mice. Using the model of multiple low-dose streptozotocin (STZ)-induced diabetes, we found that autoimmune diabetes was strongly accelerated in Ucp2-KO mice, compared with Ucp2-WT mice with increased intraislet lymphocytic infiltration. Macrophages from STZ-treated Ucp2-KO mice had increased IL-1beta and nitric oxide (NO) production, compared with WT macrophages. Moreover, more macrophages were recruited in islets of STZ-treated Ucp2-KO mice, compared with Ucp2-WT mice. This finding also was accompanied by increased NO/ROS-induced damage. Altogether, our data show that inflammation is stronger in Ucp2-KO mice and islets, leading to the exacerbated disease in these mice. Our results highlight the mitochondrial protein UCP2 as a new player in autoimmune diabetes.     

Mice lacking the thyroid hormone receptor-alpha gene spend more energy in thermogenesis, burn more fat, and are less sensitive to high-fat diet-induced obesity

Unable to activate brown adipose tissue (BAT) thermogenesis, alphaT3-receptor-deficient mice (Thra-0/0) are cold intolerant. Our objective was to investigate the impact on energy economy and mechanisms of the alternate facultative thermogenesis developed. Energy expenditure (oxygen and food consumption) is elevated in Thra-0/0 mice reared at room temperature. Such difference disappears at thermoneutrality (30 C) and expands as ambient temperature becomes colder (P < 0.001). Despite eating more, Thra-0/0 are leaner than wild-type (WT) mice (P < 0.01), whereas these, whether on chow or high-fat diet, gained more weight (g/d: 0.12 +/- 0.002 vs. 0.08 +/- 0.002 and 0.25 +/- 0.005 vs. 0.17 +/- 0.005, respectively) and adiposity than Thra-0/0 mice (P < 0.001). The respiratory quotient was lower in Thra-0/0 than WT mice (P < 0.001), after feeding or fasted, on chow or high-fat diet, indicating a preference for fat as fuel, which was associated with increased lipoprotein lipase (LPL) expression in skeletal muscle of Thra-0/0 mice but with no differences in gene expression in white adipose tissue. Type-2 deiodinase (D2) was increased in BAT and aerobic muscle of Thra-0/0 mice. This and liver D1 were increased by a high-fat diet in both genotypes, as also were serum T3 and T3/T4 ratio, but more in Thra-0/0 than WT mice (P < 0.001). Remarkably, when studied at thermoneutrality, genotype differences in weight and adiposity gain, respiratory quotient, D2, and LPL disappeared. Thus, disruption of BAT thermogenesis in Thra-0/0 mice activates an alternate facultative thermogenesis that is more energy demanding and associated with reduced fuel efficiency, leanness, increased capacity to oxidize fat, and relative resistance to diet-induced obesity, in all of which muscle LPL and deiodinases play a key role.     

Genetic ablation of phosphatidylcholine transfer protein/StarD2 in ob/ob mice improves glucose tolerance without increasing energy expenditure

ObjectivePhosphatidylcholine transfer protein (PC-TP; synonym StarD2) is highly expressed in liver and oxidative tissues. PC-TP promotes hepatic glucose production during fasting and aggravates glucose intolerance in high fat fed mice. However, because PC-TP also suppresses thermogenesis in brown adipose tissue (BAT), its direct contribution to obesity-associated diabetes in mice remains unclear. Here we examined the effects of genetic PC-TP ablation on glucose homeostasis in leptin-deficient ob/ob mice, which exhibit both diabetes and altered thermoregulation.Animals/MethodsMice lacking both PC-TP and leptin (Pctp^−/−;ob/ob) were prepared by crossing Pctp^−/− with ob/+ mice. Glucose homeostasis was assessed by standard assays, and energy expenditure was determined by indirect calorimetry using a comprehensive laboratory animal monitoring system, which also recorded physical activity and food intake. Body composition was determined by NMR and hepatic lipids by enzymatic assays. Core body temperature was measured using a rectal thermocouple probe.ResultsPctp^−/−;ob/ob mice demonstrated improved glucose homeostasis, as evidenced by markedly improved glucose and pyruvate tolerance tests, without changes in insulin tolerance. However, there were no differences in EE at any ambient temperature. There were also no effects of PC-TP expression on physical activity, food intake or core body temperature.ConclusionsImproved glucose tolerance in Pctp^−/−;ob/ob mice in the absence of increases in energy expenditure or core body temperature indicates a direct pathogenic role for PC-TP in diabetes in leptin deficient mice.