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Activated beige adipocytes have therapeutic potential due to their ability to improve glucose and lipid homeostasis. To date, the origin of beige adipocytes remains enigmatic. Whether beige cells arise through de novo differentiation from resident precursors or through reprogramming of mature white adipocytes has been a topic of intense discussion. Here, we offer our perspective on the natural origin of beige adipocytes in mice. In particular, we revisit recent lineage-tracing studies that shed light on this issue and offer new insight into how environmental housing temperatures early in life influence the mode of beige adipocyte biogenesis upon cold exposure later in life. We suggest a unified model in which beige adipocytes (UCP1+ multilocular cells) in rodents initially arise predominantly from progenitors (i.e., de novo beige adipogenesis) upon the first exposure to cold temperatures and then interconvert between “dormant beige” and “active beige” phenotypes (i.e., beige cell activation) upon subsequent changes in environmental temperature. Importantly, we highlight experimental considerations needed to visualize de novo adipogenesis versus beige cell activation in mice. A precise understanding of the cellular origins of beige adipocytes emanating in response to physiological and pharmacological stimuli may better inform therapeutic strategies to recruit beige adipocytes in vivo.

Transcripts of key enzymes in the Leloir pathway of galactose metabolism in mouse livers are significantly increased after chronic high-fat/high-sucrose feeding. UDP-galactose-4-epimerase (GALE) is the last enzyme in this pathway that converts UDP-galactose to UDP-glucose and was previously identified as a downstream target of the endoplasmic reticulum (ER) stress effector spliced X-box binding protein 1, suggesting an interesting cross talk between galactose and glucose metabolism in the context of hepatic ER stress and whole-body metabolic fitness. However, its specific role in glucose metabolism is not established. Using an inducible and tissue-specific mouse model, we report that hepatic overexpression of Gale increases gluconeogenesis from pyruvate and impairs glucose tolerance. Conversely, genetic reduction of Gale in liver improves glucose tolerance. Transcriptional profiling identifies trefoil factor 3 (Tff3) as one of the downstream targets of GALE. Restoration of Tff3 expression corrects glucose intolerance in Gale-overexpressing mice. These studies reveal a new link between hepatic GALE activity and whole-body glucose homeostasis via regulation of hepatic Tff3 expression.

Dermal adipose tissue is a layer of adipocytes residing under the reticular dermis. Recent data have revealed a difference between the dermal adipose tissue and subcutaneous adipose tissue. Dermal adipocytes show dramatic changes in synchrony with hair cycling. Beyond hair cycling, many additional stimuli can modulate the volume of dermal adipose tissue. However, dermal adipose tissue remains poorly characterized. The fate of the mature dermal adipocytes and the origin of the re-appearing dermal adipocytes after they de-differentiate are still unclear. Here we isolated dermal adipocytes and characterized dermal fat as a fat pad with unique identity. Using pulsed lineage tracing of dermal mature adipocytes, as well as single cell sequencing, we reveal that mature dermal adipocytes can de-differentiate into fibroblast-like cells or even myofibroblast-like cells. Upon various stimuli, the de-differentiated fibroblasts proliferate and re-differentiated into adipocytes. Similar to other skin fibroblasts, the de-differentiated fibroblast-like cells showed two distinct clusters, and totally lose their mature adipocyte characteristics. In addition, manipulation of dermal adipose tissue highlights an important role of adipocytes for hair cycling and wound healing. This study advances our knowledge of dermal adipose tissue and implicates dermal adipocytes as essential components for normal skin morphology and function. Disclosure Z. Zhang: None. M. Shao: None. R.K. Gupta: None. P.E. Scherer: None.

Foxa1 (formerly hepatic nuclear factor 3α) belongs to the family of Foxa genes that are expressed in early development and takes part in the differentiation of endoderm-derived organs and the regulation of glucose homeostasis. Foxa1−/− pups are growth retarded and hypoglycemic but glucose intolerant in response to an intraperitoneal glucose challenge. However, the mechanism of glucose intolerance in this model has not been investigated. Here, we show that Foxa1−/− islets exhibit decreased glucose-stimulated insulin release in islet perifusion experiments and have significantly reduced pancreatic insulin and glucagon content. Moreover, Foxa1−/− β-cells exhibit attenuated calcium influx in response to glucose and glyburide, suggesting an insulin secretion defect either at the level or upstream of the ATP-sensitive K+ channel. Intracellular ATP levels after incubation with 10 mmol/l glucose were about 2.5 times lower in Foxa1−/− islets compared with controls. This diminished ATP synthesis could be explained by increased expression of the mitochondrial uncoupling protein uncoupling protein 2 (UCP2) in Foxa1-deficient islets, resulting in partially uncoupled mitochondria. Chromatin immunoprecipitation assays indicate that UCP2 is a direct transcriptional target of Foxa1 in vivo. Thus, we have identified a novel function for Foxa1 in the regulation of oxidative phosphorylation in pancreatic β-cells.