Biology subjects

Funcke, J.-B.

Publications and source records attributed to Funcke, J.-B..

3 recordsLinked to original sources

bioRxiv2026

Non-enzymatic ABHD6 interacts with Akt-FoxO1 axis to regulate selective hepatic insulin resistance

The enzymatic function of ABHD6 on insulin secretion and insulin resistance is well documented. However, its non-enzymatic function, especially its effects on selective hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD) is completely unexplored. ABHD6 is elevated under conditions of diet-induced obesity and aging. To define the role of ABHD6 in liver physiology, we generated liver-specific ABHD6 knockout mice, as well as liver specific overexpression of native and enzymatic inactive mutant ABHD6 mouse models. We demonstrated that ABHD6 is an unidentified regulator of selective hepatic insulin resistance and contributes to MASLD and liver fibrosis. Furthermore, we found that non-enzymatic ABHD6, rather than its enzymatic form, contributes to this regulation. Mechanistically, we found that ABHD6 translocated into the nucleus and interacted with Akt/FoxO1 axis to regulate its function. In addition, knockdown of FoxO1 in primary hepatocytes or overexpression of constitutively active mutant FoxO1 by AAV approach could completely abolish the effects of ABHD6 on glucose tolerance and gluconeogenesis. Our study reveals an entirely different mechanism underlying selective hepatic insulin resistance that involves a previously unknown non-enzymatic function of ABHD6. This study opens an avenue for the development of a novel class of ABHD6 inhibitors to treat MASLD and liver fibrosis. HighlightsO_LIABHD6 expression in the liver is increased with obesity and aging. C_LIO_LIABHD6 manipulation affects selective hepatic insulin resistance, MASLD and liver fibrosis. C_LIO_LINon-enzymatic ABHD6 interacts with Akt/FoxO1 axis to regulate FoxO1 transcriptional activity. C_LIO_LIThe effects of ABHD6 on glucose tolerance and hepatic gluconeogenesis are completely dependent on FoxO1 activity. C_LI

physiology↗

bioRxiv2025

ETP-Specific Knockout Mice Reveal Endotrophin as a Key Regulator of Kidney Fibrosis in Ischemia-Reperfusion Injury Models

Endotrophin (ETP), a cleavage product of the C5 domain of collagen VI 3 (COL6A3), plays a crucial role in extracellular matrix remodeling. Previously established Col6a3 knockout (KO) mouse models primarily reflect the consequences of COL6A3 loss rather than the specific effects of ETP depletion, making it challenging to directly assess ETPs function. These models either disrupt COL6A3 along with ETP production or express functionally defective COL6A3 while maintaining ETP production. To address this limitation, we developed and validated a novel ETP knockout (ETPKO) mouse model that selectively ablates ETP while preserving Col6a3 expression. To generate the ETPKO model, we introduced lox2272 sites and a fluorescent mCherry-CAAX reporter into the Col6a3 locus, ensuring that ETP expression is turned off and reporter expression is turned on upon Cre-mediated recombination. Crossing the Col6a3-Etp+mCherry-CAAX mouse line with CMV-Cre mice yielded ETPKO mice, in which successful ETP deletion was confirmed by genomic DNA sequencing and mCherry expression. Using this model, we investigated ETPs role in kidney fibrosis. ETPKO mice subjected to unilateral or bilateral renal ischemia-reperfusion injury (IRI) exhibited complete Etp mRNA ablation with only a partial reduction in Col6a3 mRNA. Notably, ETP depletion significantly attenuated fibrosis progression, demonstrating its critical role in the pathogenesis of kidney fibrosis. The ETPKO mouse model provides a targeted and specific approach for studying ETP function independently of Col6a3 expression. These findings establish ETP as a key driver of fibrosis and position ETPKO mice as a valuable tool for elucidating ETP-mediated mechanisms in preclinical disease models.

genetics↗

bioRxiv2024

Adipogenin Dictates Adipose Tissue Expansion by Facilitating the Assembly of a Dodecameric Seipin Complex

Adipogenin (Adig) is an evolutionarily conserved microprotein and is highly expressed in adipose tissues and testis. Here, we identify Adig as a critical regulator for lipid droplet formation in adipocytes. We determine that Adig interacts directly with seipin, leading to the formation of a rigid complex. We solve the structure of the seipin/Adig complex by Cryo-EM at 2.98[A] overall resolution. Surprisingly, seipin can form two unique oligomers, undecamers and dodecamers. Adig selectively binds to the dodecameric seipin complex. We further find that Adig promotes seipin assembly by stabilizing and bridging adjacent seipin subunits. Functionally, Adig plays a key role in generating lipid droplets in adipocytes. In mice, inducible overexpression of Adig in adipocytes substantially increases fat mass, with enlarged lipid droplets. It also elevates thermogenesis during cold exposure. In contrast, inducible adipocyte-specific Adig knockout mice manifest aberrant lipid droplet formation in brown adipose tissues and impaired cold tolerance.

cell biology↗