Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes.

BACKGROUND: Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2'-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. METHODS: Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. RESULTS: All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients' phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. CONCLUSIONS: The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology

Reprogramming of hepatic fat accumulation and 'browning' of adipose tissue by the short-chain fatty acid acetate

Background/Objectives: Short-chain fatty acids, produced by microbiome fermentation of carbohydrates, have been linked to a reduction in appetite, body weight and adiposity. However, determining the contribution of central and peripheral mechanisms to these effects has not been possible. Subjects/Methods:C57BL/6 mice fed with either normal or high-fat diet were treated with nanoparticle-delivered acetate, and the effects on metabolism were investigated. Results:In the liver, acetate decreased lipid accumulation and improved hepatic function, as well as increasing mitochondrial efficiency. In white adipose tissue, it inhibited lipolysis and induced 'browning', increasing thermogenic capacity that led to a reduction in body adiposity. Conclusions:This study provides novel insights into the peripheral mechanism of action of acetate, independent of central action, including ‘browning’ and enhancement of hepatic mitochondrial function

Pain when walking: individual sensory profiles in the foot soles of torture victims - a controlled study using quantitative sensory testing

BACKGROUND: With quantitative sensory testing (QST) we recently found no differences in sensory function of the foot soles between groups of torture victims with or without exposure to falanga (beatings under the feet). Compared to matched controls the torture victims had hyperalgesia to deep mechano-nociceptive stimuli and hypoesthesia to non-noxious cutaneous stimuli. The purpose of the present paper was to extend the group analysis into individual sensory profiles of victims’ feet to explore possible relations between external violence (torture), reported pain, sensory symptoms and QST data to help clarify the underlying mechanisms. METHODS: We employed interviews and assessments of the pain and sensory symptoms and QST by investigators blinded to whether the patients, 32 male torture victims from the Middle East, had (n=15), or had not (n=17) been exposed to falanga. Pain intensity, area and stimulus dependence were used to characterize the pain. QST included thresholds for touch, cold, warmth, cold-pain, heat-pain, deep pressure pain and wind-up to cutaneous noxious stimuli. An ethnically matched control group was available.The normality criterion, from our control group data, was set as the mean +/− 1.28SD, thus including 80% of all values.QST data were transformed into three categories in relation to our normality range; hypoesthesia, normoesthesia or hyperesthesia/hyperalgesia. RESULTS: Most patients, irrespective of having been exposed to falanga or not, reported severe pain when walking. This was often associated with hyperalgesia to deep mechanical pressure. Hypoesthesia to mechanical stimuli co-occurred with numbness, burning and with deep mechanical hyperalgesia more often than not, but otherwise, a hypoesthesia to cutaneous sensory modalities did not co-occur systematically to falanga, pain or sensory symptoms. CONCLUSION: In torture victims, there seem to be overriding mechanisms, manifested by hyperalgesia to pressure pain, which is usually considered a sign of centralization. In addition there was cutaneous hypoesthesia, but since there was no obvious correlation to the localization of trauma, these findings may indicate centrally evoked disturbances in sensory transmission, that is, central inhibition. We interpret these findings as a sign of changes in central sensory processing as the unifying pathological mechanism of chronic pain in these persons

Pain when walking: individual sensory profiles in the foot soles of torture victims - a controlled study using quantitative sensory testing

Abstract Background With quantitative sensory testing (QST) we recently found no differences in sensory function of the foot soles between groups of torture victims with or without exposure to falanga (beatings under the feet). Compared to matched controls the torture victims had hyperalgesia to deep mechano-nociceptive stimuli and hypoesthesia to non-noxious cutaneous stimuli. The purpose of the present paper was to extend the group analysis into individual sensory profiles of victims’ feet to explore possible relations between external violence (torture), reported pain, sensory symptoms and QST data to help clarify the underlying mechanisms. Methods We employed interviews and assessments of the pain and sensory symptoms and QST by investigators blinded to whether the patients, 32 male torture victims from the Middle East, had (n=15), or had not (n=17) been exposed to falanga. Pain intensity, area and stimulus dependence were used to characterize the pain. QST included thresholds for touch, cold, warmth, cold-pain, heat-pain, deep pressure pain and wind-up to cutaneous noxious stimuli. An ethnically matched control group was available.The normality criterion, from our control group data, was set as the mean +/− 1.28SD, thus including 80% of all values.QST data were transformed into three categories in relation to our normality range; hypoesthesia, normoesthesia or hyperesthesia/hyperalgesia. Results Most patients, irrespective of having been exposed to falanga or not, reported severe pain when walking. This was often associated with hyperalgesia to deep mechanical pressure. Hypoesthesia to mechanical stimuli co-occurred with numbness, burning and with deep mechanical hyperalgesia more often than not, but otherwise, a hypoesthesia to cutaneous sensory modalities did not co-occur systematically to falanga, pain or sensory symptoms. Conclusion In torture victims, there seem to be overriding mechanisms, manifested by hyperalgesia to pressure pain, which is usually considered a sign of centralization. In addition there was cutaneous hypoesthesia, but since there was no obvious correlation to the localization of trauma, these findings may indicate centrally evoked disturbances in sensory transmission, that is, central inhibition. We interpret these findings as a sign of changes in central sensory processing as the unifying pathological mechanism of chronic pain in these persons.</p

The ecosystem approach to marine management in the Arctic: Opportunities and challenges for integration

Climate change is strongly impacting Arctic marine ecosystems, and the Arctic coastal communities whose identities, traditions and livelihoods are closely interconnected with the marine environment. The Ecosystem Approach (EA) is a promising approach for understanding and managing the occurring shifts in the Arctic marine ecosystems. Based on our analysis, we find that assessments conducted by international and regional instruments and institutions, most notably the Arctic Council, as well as the wealth of Indigenous knowledge present in the region, provide valuable starting points for the implementation of EA in the Arctic. Yet, mechanisms for translating knowledge into joint coordinated and integrated action in accordance with EA are currently lacking. Our analysis suggests that incremental steps can be taken now to promote the implementation of EA, while working to establish a more comprehensive governance framework. In our view, bottom-up initiatives may provide the most promising avenue for promoting the application of EA in the region under the current geopolitical circumstances. Support by civil society, Indigenous and conservation organizations, as well as global momentum will be necessary to coordinate, finance and elevate community-driven initiatives. Other opportunities we identify for advancing EA is to engage with sectoral management bodies and to advance EA through climate change adaptation measures