Hass, D. | bioRxiv Science

bioRxiv2024

Chronic intermittent fasting impairs β-cell maturation and function in adolescent mice

Intermittent fasting (IF) is a nutritional lifestyle intervention with broad metabolic benefits, but whether the impact of IF depends on the individuals age is unclear. Here, we investigated the effects of IF on systemic metabolism and pancreatic islet function in old, middle-aged, and young mice. Short-term IF improved glucose homeostasis across all age groups, without altering islet function and morphology. In contrast, while chronic IF was beneficial for adult mice, it resulted in impaired {beta}-cell function in the young. Using scRNAseq, we delineated that the {beta}-cell maturation and function score were reduced in young mice. In human islets, a similar pattern was observed in Type 1 (T1D), but not in Type 2 diabetes (T2D), suggesting that the impact of chronic IF in adolescence is linked to the development of {beta}-cell dysfunction. Our study suggests considering the duration of IF in younger people, as it may enhance rather than reduce diabetes outcomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/590140v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1676dd1org.highwire.dtl.DTLVardef@15ac993org.highwire.dtl.DTLVardef@167f577org.highwire.dtl.DTLVardef@247e4e_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LILong-term IF impairs {beta}-cell function in adolescent mice. C_LIO_LIIF-induced impaired {beta}-cell function is associated with impaired proliferative capacity and lower levels of mature cells. C_LIO_LIIF-induced impaired {beta}-cell function is associated with a transcriptional change highly conserved in type 1-, but not type 2 diabetes. C_LI

physiology↗

bioRxiv2020

HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signaling

Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we show that Heart- and neural crest derivatives-expressed protein 2 (HAND2) is an obesity-linked adipocyte transcription factor regulated by glucocorticoids and required for adipocyte differentiation in vitro. In a large cohort of humans with obesity, white adipose tissue (WAT) HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes, induced early in differentiation and responded to dexamethasone, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in human multipotent adipose-derived stem cells (hMADS) or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Using a combinatorial RNAseq approach we identified gene clusters regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.

molecular biology↗