Tim Julius Schulz

Our findings highlight the central role of bone marrow adipose tissue in the relationship between bone health, age, and metabolism. Increased marrow adipocytes produce endocrine signals, such as dipeptidyl peptidase-4, which modulate these associations. We show that women and men have distinct associations between bone turnover, age, and bone marrow adipocytes.

White adipose tissue primarily stores energy while brown adipose tissue dissipates energy as heat, holding promise for therapeutic use. Brown adipose tissue in the anterior trunk is believed to derive from the somitic mesoderm, although some depots are of partially unknown origin. Here we show that the subscapular, lateral, cervical and peri-aortic brown adipose depots, but not the interscapular depot, are in part formed by a non-somitic source. Single-cell sequencing along with genetic lineage tracing indicates that at embryonic day 9.5 the dorsal aorta compartment harbors multipotent mesenchymal progenitors expressing the transcription factor Osr1. Spreading laterally from the dorsal aortic midline, these cells contribute to adipose, cartilage and myogenic lineages. This study uncovers an alternative source of brown adipose tissue and suggests that a fraction of dorsal aorta-associated mesenchymal Osr1 ⁺ cells may represent the in vivo correlate of a multipotent progenitor cell type so far only characterized in vitro, the mesoangioblast.

Background: Depression constitutes a risk factor for osteoporosis, but underlying molecular and cellular mechanisms are not fully understood. MiRNAs influence gene expression and are carried by extracellular vesicles (EV), affecting cell-cell communication. Aims: (1) Identify the difference in miRNA expression between depressed patients and healthy controls; (2) Analyze associations of these miRNAs with bone turnover markers; (3) Analyze target genes of differentially regulated miRNAs and predict associated pathways regarding depression and bone metabolism. Methods and results: Blood samples from depressed patients ( n = 11) were obtained from a previous study and healthy controls ( n = 9) were recruited. Sociodemographic, depression diagnosis and depressive symptom (BDI-II) data were collected through questionnaires. Blood plasma was collected from each participant and real-time-quantitative PCR was performed on isolated plasma EVs; differences in miRNA expression between groups were analyzed using qbase+. Regression models assessed the associations of differentially regulated miRNAs with bone turnover markers procollagen-1 N-terminal-peptide, osteocalcin, and crosslaps; enriched pathways and miRNA target gene networks were analyzed. 19 miRNAs were differentially expressed between groups ( p  < 0.05 ). MiR-26b-5p and miR-106a-5p showed an association with procollagen-1 N-terminal-peptide; miR-330-5p and miR-377-3p were associated with osteocalcin, and miR-26b-5p, miR-34c-3p and miR-145 with crosslaps. Pathway analysis including the differentially expressed miRNAs predicted enriched pathways, including the FoxO signaling and p53 signaling pathway. Seven target genes were identified. Conclusions: MiRNAs (e.g. miR-26b-5p, miR-377-3p), genes (TNRC6B, HSPA8), and pathways (FoxO- and Hippo-signaling pathway) are identified which could be mediators between the influence of depression on bone health and could possibly serve as biomarkers in the treatment of bone diseases among people with mental disorders.

Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)−2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.

Background: The ability of skeletal muscle to respond adequately to changes in nutrient availability, known as metabolic flexibility, is essential for the maintenance of metabolic health and loss of flexibility contributes to the development of diabetes and obesity. The tumour suppressor protein, p53, has been linked to the control of energy metabolism. We assessed its role in the acute control of nutrient allocation in skeletal muscle in the context of limited nutrient availability.Methods: A mouse model with inducible deletion of the p53‐encoding gene, Trp53, in skeletal muscle was generated using the Cre‐loxP‐system. A detailed analysis of nutrient metabolism in mice with control and knockout genotypes was performed under ad libitum fed and fasting conditions and in exercised mice.Results: Acute deletion of p53 in myofibres of mice activated catabolic nutrient usage pathways even under ad libitum fed conditions, resulting in significantly increased overall energy expenditure (+10.6%; P = 0.0385) and a severe nutrient deficit in muscle characterized by depleted intramuscular glucose and glycogen levels (−62,0%; P < 0.0001 and −52.7%; P < 0.0001, respectively). This was accompanied by changes in marker gene expression patterns of circadian rhythmicity and hyperactivity (+57.4%; P = 0.0068). These metabolic changes occurred acutely, within 2–3 days after deletion of Trp53 was initiated, suggesting a rapid adaptive response to loss of p53, which resulted in a transient increase in lactate release to the circulation (+46.6%; P = 0.0115) from non‐exercised muscle as a result of elevated carbohydrate mobilization. Conversely, an impairment of proteostasis and amino acid metabolism was observed in knockout mice during fasting. During endurance exercise testing, mice with acute, muscle‐specific Trp53 inactivation displayed an early exhaustion phenotype with a premature shift in fuel usage and reductions in multiple performance parameters, including a significantly reduced running time and distance (−13.8%; P = 0.049 and −22.2%; P = 0.0384, respectively).Conclusions: These findings suggest that efficient nutrient conservation is a key element of normal metabolic homeostasis that is sustained by p53. The homeostatic state in metabolic tissues is actively maintained to coordinate efficient energy conservation and metabolic flexibility towards nutrient stress. The acute deletion of Trp53 unlocks mechanisms that suppress the activity of nutrient catabolic pathways, causing substantial loss of intramuscular energy stores, which contributes to a fasting‐like state in muscle tissue. Altogether, these findings uncover a novel function of p53 in the short‐term regulation of nutrient metabolism in skeletal muscle and show that p53 serves to maintain metabolic homeostasis and efficient energy conservation.

Introduction: Caloric restriction (CR) is a nutritional intervention that increases life expectancy while lowering the risk for cardio-metabolic disease. Its effects on bone health, however, remain controversial. For instance, CR has been linked to increased accumulation of bone marrow adipose tissue (BMAT) in long bones, a process thought to elicit detrimental effects on bone. Qualitative differences have been reported in BMAT in relation to its specific anatomical localization, subdividing it into physiological and potentially pathological BMAT. We here examine the local impact of CR on bone composition, microstructure and its endocrine profile in the context of aging.Methods: Young and aged male C57Bl6J mice were subjected to CR for 8 weeks and were compared to age-matched littermates with free food access. We assessed bone microstructure and BMAT by micro-CT, bone fatty acid and transcriptomic profiles, and bone healing.Results: CR increased tibial BMAT accumulation and adipogenic gene expression. CR also resulted in elevated fatty acid desaturation in the proximal and mid-shaft regions of the tibia, thus more closely resembling the biochemical lipid profile of the distally located, physiological BMAT. In aged mice, CR attenuated trabecular bone loss, suggesting that CR may revert some aspects of age-related bone dysfunction. Cortical bone, however, was decreased in young mice on CR and remained reduced in aged mice, irrespective of dietary intervention. No negative effects of CR on bone regeneration were evident in either young or aged mice.Discussion: Our findings indicate that the timing of CR is critical and may exert detrimental effects on bone biology if administered during a phase of active skeletal growth. Conversely, CR exerts positive effects on trabecular bone structure in the context of aging, which occurs despite substantial accumulation of BMAT. These data suggest that the endocrine profile of BMAT, rather than its fatty acid composition, contributes to healthy bone maintenance in aged mice.

Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5′ truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation.