Weight reduction and the impact on apnea-hypopnea index: A systematic meta-analysis.

Obstructive sleep apnea (OSA) is strongly associated with obesity. While the relationship between weight reduction and apnea-hypopnea index improvement has been documented, to our knowledge, it has not been quantified adequately. Therefore, this study aimed to quantify the relationship between weight reduction and AHI change. METHODS: A systematic literature search was performed using meta-analyses (PRISMA) guidelines for studies reporting AHI and weight loss in people with obesity/overweight and OSA between 2000 and 2023. A linear and quadratic model (weighted by treatment arm sample size) predicted percent change from baseline AHI against mean percent change from baseline weight. The quadratic term was statistically significant (P < 0.05), so the quadratic model (with 95 % prediction interval) was used. RESULTS: The literature search identified 27 studies/32 treatment arms: 15 using bariatric surgery and lifestyle intervention each and 2 using pharmacological interventions. Included studies were ≥3 months with weight intervention and participants had AHI ≥15/h. Weight reduction in people with OSA and obesity was associated with improvements in the severity of OSA. BMI reduction of 20 % was associated with AHI reduction of 57 %, while further weight reduction beyond 20 % in BMI was associated with a smaller effect on AHI. As the prediction intervals are relatively wide, a precise relationship could not be conclusively established. CONCLUSION: The degree of AHI index improvement was associated with the magnitude of weight reduction. The model suggests that with progress in weight reduction beyond 20 %, the incremental decrease in BMI appeared to translate to a smaller additional effect on AHI.

SATB2 preserves colon stem cell identity and mediates ileum-colon conversion via enhancer remodeling.

Adult stem cells maintain regenerative tissue structure and function by producing tissue-specific progeny, but the factors that preserve their tissue identities are not well understood. The small and large intestines differ markedly in cell composition and function, reflecting their distinct stem cell populations. Here we show that SATB2, a colon-restricted chromatin factor, singularly preserves LGR5+ adult colonic stem cell and epithelial identity in mice and humans. Satb2 loss in adult mice leads to stable conversion of colonic stem cells into small intestine ileal-like stem cells and replacement of the colonic mucosa with one that resembles the ileum. Conversely, SATB2 confers colonic properties on the mouse ileum. Human colonic organoids also adopt ileal characteristics upon SATB2 loss. SATB2 regulates colonic identity in part by modulating enhancer binding of the intestinal transcription factors CDX2 and HNF4A. Our study uncovers a conserved core regulator of colonic stem cells able to mediate cross-tissue plasticity in mature intestines.

Extensive Recovery of Embryonic Enhancer and Gene Memory Stored in Hypomethylated Enhancer DNA.

Developing and adult tissues use different cis-regulatory elements. Although DNA at some decommissioned embryonic enhancers is hypomethylated in adult cells, it is unknown whether this putative epigenetic memory is complete and recoverable. We find that, in adult mouse cells, hypomethylated CpG dinucleotides preserve a nearly complete archive of tissue-specific developmental enhancers. Sites that carry the active histone mark H3K4me1, and are therefore considered "primed," are mainly cis elements that act late in organogenesis. In contrast, sites decommissioned early in development retain hypomethylated DNA as a singular property. In adult intestinal and blood cells, sustained absence of polycomb repressive complex 2 indirectly reactivates most-and only-hypomethylated developmental enhancers. Embryonic and fetal transcriptional programs re-emerge as a result, in reverse chronology to cis element inactivation during development. Thus, hypomethylated DNA in adult cells preserves a "fossil record" of tissue-specific developmental enhancers, stably marking decommissioned sites and enabling recovery of this epigenetic memory.

The lineage-specific transcription factor CDX2 navigates dynamic chromatin to control distinct stages of intestine development.

Lineage-restricted transcription factors, such as the intestine-specifying factor CDX2, often have dual requirements across developmental time. Embryonic loss of CDX2 triggers homeotic transformation of intestinal fate, whereas adult-onset loss compromises crucial physiological functions but preserves intestinal identity. It is unclear how such diverse requirements are executed across the developmental continuum. Using primary and engineered human tissues, mouse genetics, and a multi-omics approach, we demonstrate that divergent CDX2 loss-of-function phenotypes in embryonic versus adult intestines correspond to divergent CDX2 chromatin-binding profiles in embryonic versus adult stages. CDX2 binds and activates distinct target genes in developing versus adult mouse and human intestinal cells. We find that temporal shifts in chromatin accessibility correspond to these context-specific CDX2 activities. Thus, CDX2 is not sufficient to activate a mature intestinal program; rather, CDX2 responds to its environment, targeting stage-specific genes to contribute to either intestinal patterning or mature intestinal function. This study provides insights into the mechanisms through which lineage-specific regulatory factors achieve divergent functions over developmental time.

Enhancer, transcriptional, and cell fate plasticity precedes intestinal determination during endoderm development.

After acquiring competence for selected cell fates, embryonic primordia may remain plastic for variable periods before tissue identity is irrevocably determined (commitment). We investigated the chromatin basis for these developmental milestones in mouse endoderm, a tissue with recognizable rostro-caudal patterning and transcription factor (TF)-dependent interim plasticity. Foregut-specific enhancers are as accessible and active in early midgut as in foregut endoderm, and intestinal enhancers and identity are established only after ectopic cis-regulatory elements are decommissioned. Depletion of the intestinal TF CDX2 before this cis element transition stabilizes foregut enhancers, reinforces ectopic transcriptional programs, and hence imposes foregut identities on the midgut. Later in development, as the window of chromatin plasticity elapses, CDX2 depletion weakens intestinal, without strengthening foregut, enhancers. Thus, midgut endoderm is primed for heterologous cell fates, and TFs act on a background of shifting chromatin access to determine intestinal at the expense of foregut identity. Similar principles likely govern other fate commitments.

Central metabolic sensing remotely controls nutrient-sensitive endocrine response in Drosophila via Sir2/Sirt1-upd2-IIS axis.

Endocrine signaling is central in coupling organismal nutrient status with maintenance of systemic metabolic homeostasis. While local nutrient sensing within the insulinogenic tissue is well studied, distant mechanisms that relay organismal nutrient status in controlling metabolic-endocrine signaling are less well understood. Here, we report a novel mechanism underlying the distant regulation of the metabolic endocrine response in Drosophila melanogaster We show that the communication between the fat body and insulin-producing cells (IPCs), important for the secretion of Drosophila insulin-like peptides (dILPs), is regulated by the master metabolic sensor Sir2/Sirt1. This communication involves a fat body-specific direct regulation of the JAK/STAT cytokine upd2 by Sir2/Sirt1. We have also uncovered the importance of this regulation in coupling nutrient inputs with dILP secretion, and distantly controlling insulin/IGF signaling (IIS) in the intestine. Our results provide fundamental mechanistic insights into the top-down control involving tissues that play key roles in metabolic sensing, endocrine signaling and nutrient uptake.

Fat body dSir2 regulates muscle mitochondrial physiology and energy homeostasis nonautonomously and mimics the autonomous functions of dSir2 in muscles.

Sir2 is an evolutionarily conserved NAD(+)-dependent deacetylase which has been shown to play a critical role in glucose and fat metabolism. In this study, we have perturbed Drosophila Sir2 (dSir2) expression, bidirectionally, in muscles and the fat body. We report that dSir2 plays a critical role in insulin signaling, glucose homeostasis, and mitochondrial functions. Importantly, we establish the nonautonomous functions of fat body dSir2 in regulating mitochondrial physiology and insulin signaling in muscles. We have identified a novel interplay between dSir2 and dFOXO at an organismal level, which involves Drosophila insulin-like peptide (dILP)-dependent insulin signaling. By genetic perturbations and metabolic rescue, we provide evidence to illustrate that fat body dSir2 mediates its effects on the muscles via free fatty acids (FFA) and dILPs (from the insulin-producing cells [IPCs]). In summary, we show that fat body dSir2 is a master regulator of organismal energy homeostasis and is required for maintaining the metabolic regulatory network across tissues.