Long-Term Cold Adaptation Does Not Require FGF21 or UCP1.

Brown adipose tissue (BAT)-dependent thermogenesis and its suggested augmenting hormone, FGF21, are potential therapeutic targets in current obesity and diabetes research. Here, we studied the role of UCP1 and FGF21 for metabolic homeostasis in the cold and dissected underlying molecular mechanisms using UCP1-FGF21 double-knockout mice. We report that neither UCP1 nor FGF21, nor even compensatory increases of FGF21 serum levels in UCP1 knockout mice, are required for defense of body temperature or for maintenance of energy metabolism and body weight. Remarkably, cold-induced browning of inguinal white adipose tissue (iWAT) is FGF21 independent. Global RNA sequencing reveals major changes in response to UCP1- but not FGF21-ablation in BAT, iWAT, and muscle. Markers of mitochondrial failure and inflammation are observed in BAT, but in particular the enhanced metabolic reprogramming in iWAT supports the thermogenic role of UCP1 and excludes an important thermogenic role of endogenous FGF21 in normal cold acclimation.

Extensive phenotypic characterization of a new transgenic mouse reveals pleiotropic perturbations in physiology due to mesenchymal hGH minigene expression.

The human growth hormone (hGH) minigene used for transgene stabilization in mice has been recently identified to be locally expressed in the tissues where transgenes are active and associated with phenotypic alterations. Here we extend these findings by analyzing the effect of the hGH minigene in TgC6hp55 transgenic mice which express the human TNFR1 under the control of the mesenchymal cell-specific CollagenVI promoter. These mice displayed a fully penetrant phenotype characterized by growth enhancement accompanied by perturbations in metabolic, skeletal, histological and other physiological parameters. Notably, this phenotype was independent of TNF-TNFR1 signaling since the genetic ablation of either Tnf or Tradd did not rescue the phenotype. Further analyses showed that the hGH minigene was expressed in several tissues, also leading to increased hGH protein levels in the serum. Pharmacological blockade of GH signaling prevented the development of the phenotype. Our results indicate that the unplanned expression of the hGH minigene in CollagenVI expressing mesenchymal cells can lead through local and/or systemic mechanisms to enhanced somatic growth followed by a plethora of primary and/or secondary effects such as hyperphagia, hypermetabolism, disturbed glucose homeostasis, altered hematological parameters, increased bone formation and lipid accumulation in metabolically critical tissues.

Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice.

OBJECTIVE: Recently, we have shown that Bezafibrate (BEZ), the pan-PPAR (peroxisome proliferator-activated receptor) activator, ameliorated diabetes in insulin deficient streptozotocin treated diabetic mice. In order to study whether BEZ can also improve glucose metabolism in a mouse model for fatty liver and type 2 diabetes, the drug was applied to TallyHo mice. METHODS: TallyHo mice were divided into an early (ED) and late (LD) diabetes progression group and both groups were treated with 0.5% BEZ (BEZ group) or standard diet (SD group) for 8 weeks. We analyzed plasma parameters, pancreatic beta-cell morphology, and mass as well as glucose metabolism of the BEZ-treated and control mice. Furthermore, liver fat content and composition as well as hepatic gluconeogenesis and mitochondrial mass were determined. RESULTS: Plasma lipid and glucose levels were markedly reduced upon BEZ treatment, which was accompanied by elevated insulin sensitivity index as well as glucose tolerance, respectively. BEZ increased islet area in the pancreas. Furthermore, BEZ treatment improved energy expenditure and metabolic flexibility. In the liver, BEZ ameliorated steatosis, modified lipid composition and increased mitochondrial mass, which was accompanied by reduced hepatic gluconeogenesis. CONCLUSIONS: Our data showed that BEZ ameliorates diabetes probably via reduced steatosis, enhanced hepatic mitochondrial mass, improved metabolic flexibility and elevated hepatic insulin sensitivity in TallyHo mice, suggesting that BEZ treatment could be beneficial for patients with NAFLD and impaired glucose metabolism.

Dexamethasone treatment alters insulin, leptin, and adiponectin levels in male mice as observed in DIO but does not lead to alterations of metabolic phenotypes in the offspring.

Epigenetic inheritance (EI) of metabolic phenotypes via the paternal lineage has been shown in rodent models of diet-induced obesity (DIO). However, the factors involved in soma-to-germline information transfer remain elusive. Here, we address the role of alterations in insulin, leptin, and adiponectin levels for EI of metabolic phenotypes by treating C57BL/6NTac male mice (F0) with the synthetic glucocorticoid dexamethasone and generating offspring (F1) either by in vitro fertilization or by natural fecundation. Dexamethasone treatment slightly alters F0 body composition by increasing fat mass and decreasing lean mass, and significantly improves glucose tolerance. Moreover, it increases insulin and leptin levels and reduces adiponectin levels in F0 fathers as observed in mouse models of DIO. However, these paternal changes of metabolic hormones do not alter metabolic parameters, such as body weight, body composition and glucose homeostasis in male and female F1 mice even when these are challenged with a high-fat diet. Accordingly, sperm transcriptomes are not altered by dexamethasone treatment. Our results suggest that neither increased glucocorticoid, insulin, and leptin levels, nor decreased adiponectin levels in fathers are sufficient to confer soma-to-germline information transfer in EI of obesity via the paternal lineage.

Genetic disruption of uncoupling protein 1 in mice renders brown adipose tissue a significant source of FGF21 secretion.

OBJECTIVE: Circulating fibroblast growth factor 21 (FGF21) is an important auto- and endocrine player with beneficial metabolic effects on obesity and diabetes. In humans, thermogenic brown adipose tissue (BAT) was recently suggested as a source of FGF21 secretion during cold exposure. Here, we aim to clarify the role of UCP1 and ambient temperature in the regulation of FGF21 in mice. METHODS: Wildtype (WT) and UCP1-knockout (UCP1 KO) mice, the latter being devoid of BAT-derived non-shivering thermogenesis, were exposed to different housing temperatures. Plasma metabolites and FGF21 levels were determined, gene expression was analyzed by qPCR, and tissue histology was performed with adipose tissue. RESULTS: At thermoneutrality, FGF21 gene expression and serum levels were not different between WT and UCP1 KO mice. Cold exposure led to highly increased FGF21 serum levels in UCP1 KO mice, which were reflected in increased FGF21 gene expression in adipose tissues but not in liver and skeletal muscle. Ex vivo secretion assays revealed FGF21 release only from BAT, progressively increasing with decreasing ambient temperatures. In association with increased FGF21 serum levels in the UCP1 KO mouse, typical FGF21-related serum metabolites and inguinal white adipose tissue morphology and thermogenic gene expression were altered. CONCLUSIONS: Here we show that the genetic ablation of UCP1 increases FGF21 gene expression in adipose tissue. The removal of adaptive nonshivering thermogenesis renders BAT a significant source of endogenous FGF21 under thermal stress. Thus, the thermogenic competence of BAT is not a requirement for FGF21 secretion. Notably, high endogenous FGF21 levels in UCP1-deficient models and subjects may confound pharmacological FGF21 treatments.