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Martin Klingenspor

Publications and source records attributed to Martin Klingenspor.

At least 19 recordsLinked to original sources
PubMed2026

Human brown fat metabolism associates with systemic branched-chain amino acids homeostasis.

Circulating branched-chain amino acids (BCAAs) are linked with insulin resistance, but the human tissues contributing to systemic BCAA homeostasis remain incompletely defined. Brown adipose tissue (BAT) is a metabolically active adipose depot associated with favourable insulin sensitivity, yet its role in BCAA metabolism in humans remains unclear. We tested whether human BAT metabolism is associated with circulating BCAA levels, BAT-resident BCAA-catabolic signatures, and longitudinal changes in systemic BCAA homeostasis. We studied 83 adults who underwent metabolic phenotyping, PET-CT assessment of cold-stimulated BAT metabolism, and serum metabolomic profiling at room temperature and during acute mild cold exposure. Supraclavicular BAT biopsies from 25 participants were analysed by transcriptomics and metabolomics, and 40 participants were re-examined for circulating BCAA profiles after approximately five years. Participants with high BAT metabolism had lower circulating BCAA levels than those with low BAT metabolism. Within BAT, metabolically active individuals exhibited lower relative BCAA abundance together with higher expression of genes involved in BCAA catabolism. These BAT BCAA-catabolic signatures aligned with thermogenic capacity and indices of systemic insulin sensitivity. In contrast, individuals with low BAT metabolism showed increases in circulating BCAAs over five years. Integrative analyses further linked circulating lipopolysaccharide, a marker of metabolic endotoxemia, with higher BAT BCAA and aminomalonate abundance, together with transcriptional patterns involving inflammatory and mitochondrial pathways. Together, these findings identify human BAT metabolism as a tissue phenotype linked to systemic BCAA homeostasis and extend the role of human BAT beyond thermogenesis, suggesting that BAT-associated BCAA handling may contribute to systemic metabolic health.

Humans↗
PubMed2025

A consensus guide to preclinical indirect calorimetry experiments.

Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data repository built on shared standards. This overdue initiative stands to markedly improve the accuracy and depth of efforts to interrogate mammalian metabolism. Data sharing according to established best practices will also accelerate the translation of basic findings into clinical applications for metabolic diseases afflicting global populations.

Calorimetry, Indirect↗
PubMed2007

Power matters in closing the phenotyping gap.

Much of our understanding of physiology and metabolism is derived from investigating mouse mutants and transgenic mice, and open-access platforms for standardized mouse phenotyping such as the German Mouse Clinic (GMC) are currently viewed as one powerful tool for identifying novel gene-function relationships. Phenotyping or phenotypic screening involves the comparison of wild-type control mice with their mutant or transgenic littermates. In our study, we explored the extent to which standardized phenotyping will succeed in detecting biologically relevant phenotypic differences in mice generated and provided by different collaborators. We analyzed quantitative metabolic data (body mass, energy intake, and energy metabolized) collected at the GMC under the current workflow, and used them for statistical power considerations. Our results demonstrate that there is substantial variability in these parameters among lines of wild-type C57BL/6 (B6) mice from different sources. Given this variable background noise in mice that serve as controls, subtle phenotypes in mutant or transgenic littermates may be overlooked. Furthermore, a phenotype observed in one cohort of a mutant line may not be reproducible (to the same extent) in mice coming from a different environment or supplier. In the light of these constraints, we encourage researchers to incorporate information on intrastrain variability into future study planning, or to perform advanced hierarchical analyses. Both will ultimately improve the detectability of novel phenotypes by phenotypic screening.

Animals↗
PubMed2007

Chicken ovalbumin upstream promoter transcription factor II regulates uncoupling protein 3 gene transcription in Phodopus sungorus.

BACKGROUND: Ucp3 is an integral protein of the inner mitochondrial membrane with a role in lipid metabolism preventing deleterious effects of fatty acids in states of high lipid oxidation. Ucp3 is expressed in brown adipose tissue and skeletal muscle and controlled by a transcription factor complex including PPARalpha, MyoD and the histone acetyltransferase p300. Several studies have demonstrated interaction of these factors with chicken ovalbumin upstream promoter transcription factor II (Coup-TFII). This nuclear receptor is involved in organogenesis and other developmental processes including skeletal muscle development, but also co-regulates a number of metabolic genes. In this study we in silico analyzed the upstream region of Ucp3 of the Djungarian hamster Phodopus sungorus and identified several putative response elements for Coup-TFII. We therefore investigated whether Coup-TFII is a further player in the transcriptional control of the Ucp3 gene in rodents. RESULTS: By quantitative PCR we demonstrated a positive correlation of Coup-TFII and Ucp3 mRNA expression in skeletal muscle and brown adipose tissue in response to food deprivation and cold exposure, respectively. In reporter gene assays Coup-TFII enhanced transactivation of the Ucp3 promoter conveyed by MyoD, PPARalpha, RXRalpha and/or p300. Using deletions and mutated constructs, we identified a Coup-TFII enhancer element 816-840 bp upstream of the transcriptional start site. Binding of Coup-TFII to this upstream enhancer was confirmed in electrophoretic mobility shift and supershift assays. CONCLUSION: Transcriptional regulation of the Coup-TFII gene in response to starvation and cold exposure seems to be the regulatory mechanism of Ucp3 mRNA expression in brown adipose and skeletal muscle tissue determining the final appropriate rate of transcript synthesis. These findings add a crucial component to the complex transcriptional machinery controlling expression of Ucp3. Given the substantial evidence for a function of Ucp3 in lipid metabolism, Coup-TFII may not only be a negative regulator of glucose responsive genes but also transactivate genes involved in lipid metabolism.

Animals↗
PubMed2006

Expanding the body mass range: associations between BMR and tissue morphology in wild type and mutant dwarf mice (David mice).

We sought to identify associations of basal metabolic rate (BMR) with morphological traits in laboratory mice. In order to expand the body mass (BM) range at the intra-strain level, and to minimize relevant genetic variation, we used male and female wild type mice (C3HeB/FeJ) and previously unpublished ENU-induced dwarf mutant littermates (David mice), covering a body mass range from 13.5 g through 32.3 g. BMR was measured at 30 degrees C, mice were killed by means of CO(2 )overdose, and body composition (fat mass and lean mass) was subsequently analyzed by dual X-ray absorptiometry (DEXA), after which mice were dissected into 12 (males) and 10 (females) components, respectively. Across the 44 individuals, 43% of the variation in the basal rates of metabolism was associated with BM. The latter explained 47% to 98% of the variability in morphology of the different tissues. Our results demonstrate that sex is a major determinant of body composition and BMR in mice: when adjusted for BM, females contained many larger organs, more fat mass, and less lean mass compared to males. This could be associated with a higher mass adjusted BMR in females. Once the dominant effects of sex and BM on BMR and tissue mass were removed, and after accounting for multiple comparisons, no further significant association between individual variation in BMR and tissue mass emerged.

Animals↗
PubMed2006

Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase.

Fat tissue is the most important energy depot in vertebrates. The release of free fatty acids (FFAs) from stored fat requires the enzymatic activity of lipases. We showed that genetic inactivation of adipose triglyceride lipase (ATGL) in mice increases adipose mass and leads to triacylglycerol deposition in multiple tissues. ATGL-deficient mice accumulated large amounts of lipid in the heart, causing cardiac dysfunction and premature death. Defective cold adaptation indicated that the enzyme provides FFAs to fuel thermogenesis. The reduced availability of ATGL-derived FFAs leads to increased glucose use, increased glucose tolerance, and increased insulin sensitivity. These results indicate that ATGL is rate limiting in the catabolism of cellular fat depots and plays an important role in energy homeostasis.

Adipocytes↗
PubMed2006

Photoperiodic regulation of insulin receptor mRNA and intracellular insulin signaling in the arcuate nucleus of the Siberian hamster, Phodopus sungorus.

During the last 5 years it has been well established that photoperiod-induced changes in body weight in the seasonal hamster, Phodopus sungorus, are accompanied by a marked seasonal cycle in leptin sensitivity. In the present study, we investigated the possible involvement of insulin signaling in seasonal body weight regulation. We analyzed the expression pattern and relative intensity of insulin receptor (IR), phosphatidylinositol 3-kinase (PI3-kinase), and protein tyrosine phosphatase 1B (PTP1B) mRNAs by in situ hybridization in the brains of juvenile female hamsters acclimated to either long- (LD) or short-day length (SD) for 8 wk, with or without superimposed food deprivation for 48 h. Furthermore, the hypothalamic concentration and distribution of phospho-AKT, a marker of PI3-kinase activity was determined by immunoblotting and immunohistochemistry. Eight weeks of acclimation to SD led to a substantial downregulation of IR, PTP1B gene expression, and phospho-AKT concentration in this brain region, whereas PI3-kinase mRNA was unchanged. Food deprivation induced a decrease in PTP1B and a trend toward lowered IR gene expression in LD but not in SD. Additionally, a striking increase in PTP1B gene expression in the thalamus was observed after food deprivation in both photoperiods. The direction of change in neuronal insulin signaling contrasts to the central catabolic nature of this pathway described in other species. SD-induced reduction in insulin signaling may be due to decline in body fat stores mediated by enhanced central leptin sensitivity. Increased anorexigenic tone of leptin may overwrite central insulin signaling to prevent catabolic overdrive.

Animals↗
PubMed2005

Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis.

Acute cold exposure leads to norepinephrine release in brown adipose tissue (BAT) and activates uncoupling protein (UCP)1-mediated nonshivering thermogenesis. Chronic sympathetic stimulation is known to initiate mitochondrial biogenesis, UCP1 expression, hyperplasia of BAT, and recruitment of brown adipocytes in white adipose tissue (WAT) depots. Despite distinct functions of BAT and WAT in energy balance, only a few genes are exclusively expressed in either tissue. We identified NUR77 (Nr4a1), an orphan receptor, to be induced transiently in brown adipocytes in response to beta-adrenergic stimulation and in BAT of cold-exposed mice. Subsequent reporter gene assays demonstrated an inhibitory action of NUR77 on basal and peroxisome proliferator-activated receptor (PPAR)gamma/retinoid X receptor (RXR)alpha-mediated transactivation of the Ucp1 enhancer in heterologous cotransfection experiments. Despite this function of NUR77 in the control of Ucp1 gene expression, nonshivering thermogenesis was not affected in Nur77 knockout mice. However, we observed a superinduction of Nor1 in BAT of cold-exposed knockout mice. We conclude that NUR77 is a cold-induced negative regulator of Ucp1, but phenotypic consequences in knockout mice are compensated by functional redundancy of Nor1.

Adipose Tissue, Brown↗
PubMed2005

Uncoupling protein 1 in fish uncovers an ancient evolutionary history of mammalian nonshivering thermogenesis.

Uncoupling proteins (UCPs) increase proton leakage across the inner mitochondrial membrane. Thereby, UCP1 in brown adipose tissue dissipates proton motive force as heat. This mechanism of nonshivering thermogenesis is considered as a monophyletic trait of endothermic placental mammals that emerged about 140 million years ago and provided a crucial advantage for life in the cold. The paralogues UCP2 and UCP3 are probably not thermogenic proteins but convey mild uncoupling, which may serve to reduce the rate of mitochondrial reactive oxygen species production. Both are present in endotherms (mammals and birds), but so far only UCP2 has been identified in ectothermic vertebrates (fish and amphibia). The evolution of UCPs is of general interest in the search for the origin of mammalian UCP1-mediated nonshivering thermogenesis. We here show the presence of UCP1 and UCP3 in ectothermic teleost fish species using comparative genomics, phylogenetic inference, and gene expression analysis. In the common carp (Cyprinus carpio), UCP1 is predominantly expressed in the liver and strongly diminished in response to cold exposure, thus contrasting the cold-induced expression of mammalian UCP1 in brown adipose tissue. UCP3 mRNA is only found in carp skeletal muscle with expression levels increased fivefold in response to fasting. Our findings disprove the monophyletic nature of UCP1 in placental mammals and demonstrate that all three members of the core UCP family were already present before the divergence of ray-finned and lobe-finned vertebrate lineages about 420 million years ago.

Amino Acid Sequence↗
PubMed2005

A role for brain-derived neurotrophic factor in B cell development.

In the present study, we demonstrated a significant reduction of B lymphocytes in the blood, spleen and bone marrow of BDNF deficient mice. The observed developmental block in bone marrow B cell development was linked specifically to the Pre-BII stage. B lymphocytes express the BDNF receptors p75NTR and TrkB(gp95), while no BDNF expression was found. However, a strong BDNF expression was demonstrated in bone marrow stromal cells. An increase of intracellular free calcium [Ca2+]i in B lymphocytes after BDNF application confirms a direct responsiveness of B lymphocytes to BDNF. In conclusion, these results suggest a role of BDNF for normal B lymphocyte development through paracrine effects in the bone marrow.

Animals↗
PubMed2005

Neuronal distribution of melanin-concentrating hormone, cocaine- and amphetamine-regulated transcript and orexin B in the brain of the Djungarian hamster (Phodopus sungorus).

The distribution of melanin-concentrating hormone-, cocaine- and amphetamine-regulated transcript- and orexin B-immunoreactive elements as well as their morphological relationships in selected brain structures harbouring the neuroendocrine pathways controlling energy balance and circadian rhythmicity in the Djungarian hamster (Phodopus sungorus) were studied. Cocaine- and amphetamine-regulated transcript-(55-102)-immunoreactive perikarya co-expressed melanin-concentrating hormone-immunoreactivity in the lateral hypothalamic area, dorsomedial hypothalamic nucleus, zona incerta and posterior hypothalamic area. In addition, arcuate nucleus, hypothalamic periventricular nucleus, Edinger-Westphal nucleus, and the rostral aspect of the dorsal raphe nucleus contained cocaine- and amphetamine-regulated transcript-immunoreactive cell profiles. Orexin B-immunoreactive perikarya were distributed in the lateral hypothalamic area, dorsomedial hypothalamic nucleus and retrochiasmatic area. Cells immunoreactive for orexin B did not co-express melanin-concentrating hormone-immunoreactivity, but orexin B-immunoreactive fibers had close apposition to many melanin-concentrating hormone-immunoreactive cells. Whereas immunoreactivity for all examined peptides was absent in the suprachiasmatic nucleus, dense and large orexin B-immunoreactive fibers and to a lesser extent melanin-concentrating hormone- and cocaine- and amphetamine-regulated transcript-immunoreactive fibers of smaller size were present in the intergeniculate leaflet and raphe nucleus. These observations in Djungarian hamsters indicate that the neuronal distribution of the examined peptides is strongly conserved between species. In addition, the presence of fibers within the neuronal components of the circadian timing system suggests that they may indirectly influence circadian rhythms.

Animals↗
PubMed2004

Depression of transcription and translation during daily torpor in the Djungarian hamster (Phodopus sungorus).

During daily torpor, Djungarian hamsters reduce their metabolic rate by more than 70% below their resting metabolic rate for several hours per day. We investigated whether this depression of metabolism is associated with a reduction in transcription and translation. Liver tissue was sampled in defined metabolic states: during normometabolism, in the torpid state and after arousal from torpor. Nuclei were isolated from liver tissue and subjected to nuclear run-on assays at an assay temperature of 25 degrees C. We observed a approximately 40% decrease in transcriptional initiation in liver nuclei of hamsters which had attained minimal metabolic rate during torpor as compared to nuclei from normometabolic hamsters. During arousal from torpor, the transcriptional run-on activity recovered to the normometabolic level. Polysome profile analysis of liver tissue was used to determine the proportion of actively translating polysomes. Profiles of liver samples from torpid animals show a disaggregation of polysomes compared to profiles from normometabolic hamsters, which indicates that, in addition to transcription, protein synthesis decreases during torpor. These results indicate that during torpor a specific inhibition of the energetically costly processes of RNA and protein synthesis contributes to the overall metabolic depression.

Adaptation, Physiological↗
PubMed2004

Uncoupling protein 2 and 3 in marsupials: identification, phylogeny, and gene expression in response to cold and fasting in Antechinus flavipes.

We searched for the presence of uncoupling protein genes so far unknown in marsupials and monotremes and identified uncoupling protein 2 (UCP2) and UCP3 full-length cDNAs in libraries constructed from the marsupials Antechinus flavipes and Sminthopsis macroura. Marsupial UCP2 is 89-90% identical to rodent UCP2, whereas UCP3 exhibits 80% identity to mouse UCP3. A phylogenetic tree including all known UCPs positions the novel marsupial UCP2 and UCP3 at the base of the mammalian orthologs. In the 5'-untranslated region of UCP2 a second open reading frame encoding for a 36-amino acid peptide was identified which is highly conserved in all vertebrate UCP2 transcripts. Analysis of tissue specificity in A. flavipes with homologous cDNA probes revealed ubiquitous presence of UCP2 mRNA and striated muscle specificity of UCP3 mRNA resembling the known expression pattern in rodents. Neither UCP2 nor UCP3 gene expression was stimulated in adipose tissue and skeletal muscle of cold exposed A. flavipes. However, UCP3 mRNA expression was upregulated 6-fold in heart and 2.5-fold in skeletal muscle as reported for rodents in response to fasting. Furthermore, UCP3 mRNA seems to be coregulated with PDK4 mRNA, indicating a relation to enhanced lipid metabolism. In contrast, UCP2 gene expression was not regulated in response to fasting in adipose tissue and skeletal muscle but was diminished in the lung and increased in adipose tissue. Taken together, the sequence analysis, tissue specificity and physiological regulation suggest a conserved function of UCP2 and UCP3 during 130 million years of mammalian evolution.

Amino Acid Sequence↗
PubMed2004

A novel missense mutation in the mouse growth hormone gene causes semidominant dwarfism, hyperghrelinemia, and obesity.

The SMA1-mouse is a novel ethyl-nitroso-urea (ENU)-induced mouse mutant that carries an a-->g missense mutation in exon 5 of the GH gene, which translates to a D167G amino acid exchange in the mature protein. Mice carrying the mutation are characterized by dwarfism, predominantly due to the reduction (sma1/+) or absence (sma1/sma1) of the GH-mediated peripubertal growth spurt, with sma1/+ mice displaying a less pronounced phenotype. All genotypes are viable and fertile, and the mode of inheritance is in accordance with a semidominant Mendelian trait. Adult SMA1 mice accumulate excessive amounts of sc and visceral fat in the presence of elevated plasma ghrelin levels, possibly reflecting altered energy partitioning. Our results suggest impaired storage and/or secretion of pituitary GH in mutants, resulting in reduced pituitary GH and reduced GH-stimulated IGF-1 expression. Generation and identification of the SMA1 mouse exemplifies the power of the combination of random mouse mutagenesis with a highly detailed phenotype-analysis as a successful strategy for the detection and analysis of novel gene-function relationships.

Adipose Tissue↗
PubMed2004

Gene or size: metabolic rate and body temperature in obese growth hormone-deficient dwarf mice.

OBJECTIVE: SMA1 mice carry a missense mutation in the growth hormone gene that leads to semidominant dwarfism and obesity. In this study, the basic thermal and metabolic properties of SMA1 mice were examined to detect metabolic alterations that can support the accretion of excess fat. RESEARCH METHODS AND PROCEDURES: Basal and resting metabolic rates (RMRs) in wild-type and SMA1 (sma1/+ and sma1/sma1) mice were determined by indirect calorimetry. Body temperature (T(b)) was recorded using intraperitoneally implanted temperature-sensitive transmitters, and body composition was determined by DXA. RESULTS: SMA1 mice have proportionally lower basal and resting metabolic rates, higher body mass (BM)-specific RMRs, and a higher lower critical temperature, and display a decrease in T(b) by 0.4 degrees C in sma1/+ and 0.9 degrees C in sma1/sma1. DISCUSSION: The analysis of gene effects on BM and energy expenditure in mouse mutants must consider the appropriate allometric relationship between BM and metabolic rate. With the exception of T(b), all metabolic alterations observed in SMA1 reflect reduced size.

Animals↗
PubMed2003

Photoperiodic regulation of leptin sensitivity in the Siberian hamster, Phodopus sungorus, is reflected in arcuate nucleus SOCS-3 (suppressor of cytokine signaling) gene expression.

We present the first evidence that suppressor of cytokine signaling-3 (SOCS3), a protein inhibiting Janus kinase/signal transducer and activator of transcription (STAT) signaling distal of the leptin receptor, conveys seasonal changes in leptin sensitivity in the Siberian hamster. Food deprivation (48 h) reduced SOCS3 gene expression in hamsters acclimated to either long (LD) or short (SD) photoperiods, suggesting that leptin signals acute starvation regardless of photoperiod. However, SOCS3 mRNA levels were substantially lower in the hypothalamic arcuate nucleus of hamsters acclimated to SD than in those raised in LD. In juveniles raised in LD, a rapid increase in SOCS3 mRNA was observed within 4 d of weaning, which was completely prevented by transfer to SD on the day of weaning. The early increase in SOCS3 gene expression in juvenile hamsters in LD clearly preceded the establishment of different body weight trajectories in LD and SD. In adult LD hamsters, SOCS3 mRNA was maintained at an elevated level despite the chronic food restriction imposed to lower body weight and serum leptin to or even below SD levels. A single injection of leptin in SD hamsters elevated SOCS3 mRNA to LD levels, whereas leptin treatment had no effect on SOCS3 gene expression in LD hamsters. Our results suggest that the development of leptin resistance in LD-acclimated hamsters involves SOCS3-mediated suppression of leptin signaling in the arcuate nucleus. Increased SOCS3 expression in LD hamsters is independent of body fat and serum leptin levels, suggesting that the photoperiod is able to trigger the biannual reversible switch in leptin sensitivity.

Acclimatization↗
PubMed2003

Normal distribution of body weight gain in male Sprague-Dawley rats fed a high-energy diet.

OBJECTIVE: To investigate the effect of a high-energy (HE) diet on caloric intake, body weight, and related parameters in outbred male Sprague-Dawley (SD) rats. RESEARCH METHODS AND PROCEDURES: Twenty-eight SD rats were fed either chow (C) for 19 weeks or HE diet for 14 weeks and then C for 5 weeks. Blood hormones and metabolites were assayed, and expression of uncoupling protein-1 and hypothalamic energy-balance-related genes were determined by Northern blotting and in situ hybridization, respectively. RESULTS: HE rats gained body weight more rapidly than C animals with a range of weight gains, but there was no evidence that weight gain was bimodally distributed. Caloric intake was transiently elevated after introduction of the HE diet. Transfer of HE rats back to C resulted in a drop in caloric intake, but a stable body weight. In terminal analysis, two of four dissected adipose tissue depots were heavier in rats that had previously been fed HE diet. Blood leptin, insulin, glucose, and nonesterified fatty acids were not different between the groups. Uncoupling protein-1 mRNA was elevated in interscapular brown adipose tissue from HE rats. There was a trend for agouti-related peptide mRNA in the hypothalamic arcuate nucleus to be higher in HE rats. DISCUSSION: Contrary to other studies of the SD rat on HE diet, body weight and other measured parameters were normally distributed. There was no segregation into two distinct populations on the basis of susceptibility to diet-induced obesity. This characteristic may be dependent on the breeding colony from which animals were sourced.

Adipose Tissue↗