The islet-expressed Lhx1 transcription factor interacts with Islet-1 and contributes to glucose homeostasis

Bethea, Maigen; Liu, Yanping; Wade, Alexa K.; Mullen, Rachel D.; Gupta, Rajesh; Gelfanov, Vasily; DiMarchi, Richard D.; Bhatnagar, Sushant; Behringer, Richard R.; Habegger, Kirk M.; Hunter, Chad S.

doi:10.1152/ajpendo.00235.2018

Cited by 11 publications

(14 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lhx1, 2, and 3 are LIM-HD transcription factors related to Isl1, and are critical for regulating organogenesis and development of neuronal and hematopoietic systems [84], which are also important for normal islet function. Lhx1 has been shown to act as a novel regulator of islet function, which interacting with Isl1 and LIM domain-binding protein 1 (Ldb1) and maintaining glucose homeostasis via regulating the expression of glucagon-like peptide 1 receptor (Glp1R) [85]. Indeed, Lhx1 was predicted as an inhibited upstream regulator in both 2-wk and 10-wk IUGR islets in our transcriptome datasets [9].…”

Section: Ten-week-old Animalsmentioning

confidence: 90%

Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats

Lien

Wang

et al. 2020

Cells

View full text Add to dashboard Cite

Intrauterine growth retardation (IUGR), which induces epigenetic modifications and permanent changes in gene expression, has been associated with the development of type 2 diabetes. Using a rat model of IUGR, we performed ChIP-Seq to identify and map genome-wide histone modifications and gene dysregulation in islets from 2- and 10-week rats. IUGR induced significant changes in the enrichment of H3K4me3, H3K27me3, and H3K27Ac marks in both 2-wk and 10-wk islets, which were correlated with expression changes of multiple genes critical for islet function in IUGR islets. ChIP-Seq analysis showed that IUGR-induced histone mark changes were enriched at critical transcription factor binding motifs, such as C/EBPs, Ets1, Bcl6, Thrb, Ebf1, Sox9, and Mitf. These transcription factors were also identified as top upstream regulators in our previously published transcriptome study. In addition, our ChIP-seq data revealed more than 1000 potential bivalent genes as identified by enrichment of both H3K4me3 and H3K27me3. The poised state of many potential bivalent genes was altered by IUGR, particularly Acod1, Fgf21, Serpina11, Cdh16, Lrrc27, and Lrrc66, key islet genes. Collectively, our findings suggest alterations of histone modification in key transcription factors and genes that may contribute to long-term gene dysregulation and an abnormal islet phenotype in IUGR rats.

show abstract

Section: Ten-week-old Animalsmentioning

confidence: 90%

Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats

Lien

Wang

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…Fluorescent immunohistochemistry. Pancreata were dissected from the 1153-treated cohort and fixed overnight in 4% formaldehyde diluted in 1× PBS at 4°C, then embedded in paraffin or OCT (Tissue-Tek 4583) as previously described (74). Sections were cut to 6 μm and then blocked using 5% normal donkey serum in 1% bovine serum albumin in 1× PBS for 1 hour at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Glucagon-receptor signaling regulates weight loss via central KLB receptor complexes

Nason¹,

Antipenko²,

Presedo³

et al. 2021

JCI Insight

Self Cite

View full text Add to dashboard Cite

Glucagon regulates glucose and lipid metabolism and promotes weight loss. Thus, therapeutics stimulating glucagon receptor (GCGR) signaling are promising for obesity treatment; however, the underlying mechanism(s) have yet to be fully elucidated. We previously identified that hepatic GCGR signaling increases circulating fibroblast growth factor 21 (FGF21), a potent regulator of energy balance. We reported that mice deficient for liver Fgf21 are partially resistant to GCGR-mediated weight loss, implicating FGF21 as a regulator of glucagon’s weight loss effects. FGF21 signaling requires an obligate coreceptor (β-Klotho, KLB), with expression limited to adipose tissue, liver, pancreas, and brain. We hypothesized that the GCGR-FGF21 system mediates weight loss through a central mechanism. Mice deficient for neuronal Klb exhibited a partial reduction in body weight with chronic GCGR agonism (via IUB288) compared with controls, supporting a role for central FGF21 signaling in GCGR-mediated weight loss. Substantiating these results, mice with central KLB inhibition via a pharmacological KLB antagonist, 1153, also displayed partial weight loss. Central KLB, however, is dispensable for GCGR-mediated improvements in plasma cholesterol and liver triglycerides. Together, these data suggest GCGR agonism mediates part of its weight loss properties through central KLB and has implications for future treatments of obesity and metabolic syndrome.

show abstract

“…siRNA transfections [ 20 ] were conducted with the Ucp1 -expressing X9 adipocyte cell line as previously described [ 21 ]. These cells were induced similarly to the SVF experiment detailed above.…”

Section: Methodsmentioning

confidence: 99%

“…Western blotting was performed as described previously [ 20 , 24 ]. Polyvinylidene difluoride (PVDF) membranes were probed using the following primary antibodies: rabbit α-LDB1 (1:1000, generously provided by Dr. Paul Love, NIH), rabbit α-UCP1 (1:1000, Cell Signaling #14670S (D9D6X)), mouse a-Actin (1:1000, Abcam ab3280), rabbit α-pAKT S473 (1:1000, Cell Signaling #9271S), rabbit Pan AKT (1:3000, Cell Signaling #4691S), rabbit α-phospho-p44/42 MAPK (T202/4204) (1:1000, Cell Signaling #4370S), and rabbit α-p44/42 MAPK (T202/4204) (1:1000, Cell Signaling #4695S).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The transcriptional co-regulator LDB1 is required for brown adipose function

Kepple

Liu

Kim

et al. 2021

Molecular Metabolism

Self Cite

View full text Add to dashboard Cite

Objective Brown adipose tissue (BAT) is critical for thermogenesis and glucose/lipid homeostasis. Exploiting the energy uncoupling capacity of BAT may reveal targets for obesity therapies. This exploitation requires a greater understanding of the transcriptional mechanisms underlying BAT function. One potential regulator of BAT is the transcriptional co-regulator LIM domain-binding protein 1 (LDB1), which acts as a dimerized scaffold, allowing for the assembly of transcriptional complexes. Utilizing a global LDB1 heterozygous mouse model, we recently reported that LDB1 might have novel roles in regulating BAT function. However, direct evidence for the LDB1 regulation of BAT thermogenesis and substrate utilization has not been elucidated. We hypothesize that brown adipocyte-expressed LDB1 is required for BAT function. Methods LDB1-deficient primary cells and brown adipocyte cell lines were assessed via qRT-PCR and western blotting for altered mRNA and protein levels to define the brown adipose-specific roles. We conducted chromatin immunoprecipitation with primary BAT tissue and immortalized cell lines. Potential transcriptional partners of LDB1 were revealed by conducting LIM factor surveys via qRT-PCR in mouse and human brown adipocytes. We developed a Ucp1 -Cre-driven LDB1-deficiency mouse model, termed Ldb1 ΔBAT , to test LDB1 function in vivo . Glucose tolerance and uptake were assessed at thermoneutrality via intraperitoneal glucose challenge and glucose tracer studies. Insulin tolerance was measured at thermoneutrality and after stimulation with cold or the administration of the β3-adrenergic receptor (β3-AR) agonist CL316,243. Additionally, we analyzed plasma insulin via ELISA and insulin signaling via western blotting. Lipid metabolism was evaluated via BAT weight, histology, lipid droplet morphometry, and the examination of lipid-associated mRNA. Finally, energy expenditure and cold tolerance were evaluated via indirect calorimetry and cold challenges. Results Reducing Ldb1 in vitro and in vivo resulted in altered BAT-selective mRNA, including Ucp1 , Elovl3 , and Dio2 . In addition, there was reduced Ucp1 induction in vitro . Impacts on gene expression may be due, in part, to LDB1 occupying Ucp1 upstream regulatory domains. We also identified BAT-expressed LIM-domain factors Lmo2 , Lmo4 , and Lhx8 , which may partner with LDB1 to mediate activity in brown adipocytes. Additionally, we observed LDB1 enrichment in human brown adipose. In vivo analysis revealed LDB1 i...

show abstract

The islet-expressed Lhx1 transcription factor interacts with Islet-1 and contributes to glucose homeostasis

Cited by 11 publications

References 59 publications

Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats

Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats

Glucagon-receptor signaling regulates weight loss via central KLB receptor complexes

The transcriptional co-regulator LDB1 is required for brown adipose function

Contact Info

Product

Resources

About