Stanford Advisors

All Publications

  • Sirtuin1-Mediated Deacetylation of Hypothalamic TTF-1 Contributes to the Energy Deficiency Response INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Kang, D., Yang, H., Kim, D., Kim, K., Jeong, B., Park, B., Park, J., Kim, J., Lee, B. 2023; 24 (15)


    TTF-1 stimulates appetite by regulating the expression of agouti-related peptide (AgRP) and proopiomelanocortin (POMC) genes in the hypothalamus of starving animals. However, the mechanism underlying TTF-1's response to decreased energy levels remains elusive. Here, we provide evidence that the NAD+-dependent deacetylase, sirtuin1 (Sirt1), activates TTF-1 in response to energy deficiency. Energy deficiency leads to a twofold increase in the expression of both Sirt1 and TTF-1, leading to the deacetylation of TTF-1 through the interaction between the two proteins. The activation of Sirt1, induced by energy deficiency or resveratrol treatment, leads to a significant increase in the deacetylation of TTF-1 and promotes its nuclear translocation. Conversely, the inhibition of Sirt1 prevents these Sirt1 effects. Notably, a point mutation in a lysine residue of TTF-1 significantly disrupts its deacetylation and thus nearly completely hinders its ability to regulate AgRP and POMC gene expression. These findings highlight the importance of energy-deficiency-induced deacetylation of TTF-1 in the control of AgRP and POMC gene expression.

    View details for DOI 10.3390/ijms241512530

    View details for Web of Science ID 001045646900001

    View details for PubMedID 37569904

    View details for PubMedCentralID PMC10419861

  • Bridging Energy Need and Feeding Behavior: The Impact of eIF2α Phosphorylation in AgRP Neurons. Diabetes Kim, K. K., Lee, T. H., Park, B. S., Kang, D., Kim, D. H., Jeong, B., Kim, J. W., Yang, H. R., Kim, H. R., Jin, S., Back, S. H., Park, J. W., Kim, J. G., Lee, B. J. 2023


    Eukaryotic translation initiation factor 2α (eIF2α) is a key mediator of the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR). In mammals, eIF2α is phosphorylated by overnutrition-induced ER stress and is related to the development of obesity. Here, we studied the function of phosphorylated eIF2α (p-eIF2α) in AgRP neurons using a mouse model (AgRPeIF2αA/A) with an AgRP neuron-specific substitution from Ser 51 to Ala in eIF2α, which impairs eIF2α phosphorylation in AgRP neurons. These AgRPeIF2αA/A mice showed decreases in starvation-induced AgRP neuronal activity and food intake and also revealed an increased responsiveness to leptin. Intriguingly, impairment of eIF2α phosphorylation produced decreases in the starvation-induced expression of UPR and autophagy genes in AgRP neurons. Collectively, these findings suggest that eIF2α phosphorylation regulates AgRP neuronal activity by affecting intracellular responses such as the UPR and autophagy during starvation, thereby participating in the homeostatic control of wholebody energy metabolism.

    View details for DOI 10.2337/db23-0004

    View details for PubMedID 37478284

  • Hypothalamic TTF-1 orchestrates the sensitivity of leptin MOLECULAR METABOLISM Park, B., Kang, D., Kim, K., Jeong, B., Lee, T., Park, J., Kimura, S., Yeh, J., Roh, G., Lee, C., Yang, S., Yang, S., Kim, J., Lee, B. 2022; 66: 101636


    Thyroid transcription factor-1 (TTF-1), a homeodomain-containing transcription factor, is predominantly expressed in discrete areas of the hypothalamus, which acts as the central unit for the regulation of whole-body energy homeostasis. Current study designed to identify the roles of TTF-1 on the responsiveness of the hypothalamic circuit activity to circulating leptin and the development of obesity linked to the insensitivity of leptin.We generated conditional knock-out mice by crossing TTF-1flox/flox mice with leptin receptor (ObRb)Cre or proopiomelanocortin (POMC)Cre transgenic mice to interrogate the contributions of TTF-1 in leptin signaling and activity. Changes of food intake, body weight and energy expenditure were evaluated in standard or high fat diet-treated transgenic mice by using an indirect calorimetry instrument. Molecular mechanism was elucidated with immunohistochemistry, immunoblotting, quantitative PCR, and promoter assays.The selective deletion of TTF-1 gene expression in cells expressing the ObRb or POMC enhanced the anorexigenic effects of leptin as well as the leptin-induced phosphorylation of STAT3. We further determined that TTF-1 inhibited the transcriptional activity of the ObRb gene. In line with these findings, the selective deletion of the TTF-1 gene in ObRb-positive cells led to protective effects against diet-induced obesity via the amelioration of leptin resistance.Collectively, these results suggest that hypothalamic TTF-1 participates in the development of obesity as a molecular component involved in the regulation of cellular leptin signaling and activity. Thus, TTF-1 may represent a therapeutic target for the treatment, prevention, and control of obesity.

    View details for DOI 10.1016/j.molmet.2022.101636

    View details for Web of Science ID 000905344500006

    View details for PubMedID 36375792

    View details for PubMedCentralID PMC9700031

  • Spexin Regulates Hypothalamic Leptin Action on Feeding Behavior BIOMOLECULES Jeong, B., Kim, K., Lee, T., Kim, H., Park, B., Park, J., Jeong, J., Seong, J., Lee, B. 2022; 12 (2)


    Spexin (SPX) is a recently identified neuropeptide that is believed to play an important role in the regulation of energy homeostasis. Here, we describe a mediating function of SPX in hypothalamic leptin action. Intracerebroventricular (icv) SPX administration induced a decrease in food intake and body weight gain. SPX was found to be expressed in cells expressing leptin receptor ObRb in the mouse hypothalamus. In line with this finding, icv leptin injection increased SPX mRNA in the ObRb-positive cells of the hypothalamus, which was blocked by treatment with a STAT3 inhibitor. Leptin also increased STAT3 binding to the SPX promoter, as measured by chromatin immunoprecipitation assays. In vivo blockade of hypothalamic SPX biosynthesis with an antisense oligodeoxynucleotide (AS ODN) resulted in a diminished leptin effect on food intake and body weight. AS ODN reversed leptin's effect on the proopiomelanocortin (POMC) mRNA expression and, moreover, decreased leptin-induced STAT3 binding to the POMC promoter sequence. These results suggest that SPX is involved in leptin's action on POMC gene expression in the hypothalamus and impacts the anorexigenic effects of leptin.

    View details for DOI 10.3390/biom12020236

    View details for Web of Science ID 000767702800001

    View details for PubMedID 35204737

    View details for PubMedCentralID PMC8961618

  • Transcription Factor TonEBP Stimulates Hyperosmolality-Dependent Arginine Vasopressin Gene Expression in the Mouse Hypothalamus FRONTIERS IN ENDOCRINOLOGY Kim, D., Kim, K., Lee, T., Eom, H., Kim, J., Park, J., Jeong, J., Lee, B. 2021; 12: 627343


    The hypothalamic neuroendocrine system is strongly implicated in body energy homeostasis. In particular, the degree of production and release of arginine vasopressin (AVP) in the hypothalamus is affected by plasma osmolality, and that hypothalamic AVP is responsible for thirst and osmolality-dependent water and metabolic balance. However, the osmolality-responsive intracellular mechanism within AVP cells that regulates AVP synthesis is not clearly understood. Here, we report a role for tonicity-responsive enhancer binding protein (TonEBP), a transcription factor sensitive to cellular tonicity, in regulating osmosensitive hypothalamic AVP gene transcription. Our immunohistochemical work shows that hypothalamic AVP cellular activity, as recognized by c-fos, was enhanced in parallel with an elevation in TonEBP expression within AVP cells following water deprivation. Interestingly, our in vitro investigations found a synchronized pattern of TonEBP and AVP gene expression in response to osmotic stress. Those results indicate a positive correlation between hypothalamic TonEBP and AVP production during dehydration. Promoter and chromatin immunoprecipitation assays confirmed that TonEBP can bind directly to conserved binding motifs in the 5'-flanking promoter regions of the AVP gene. Furthermore, dehydration- and TonEBP-mediated hypothalamic AVP gene activation was reduced in TonEBP haploinsufficiency mice, compared with wild TonEBP homozygote animals. Therefore, our result support the idea that TonEBP is directly necessary, at least in part, for the elevation of AVP transcription in dehydration conditions. Additionally, dehydration-induced reductions in body weight were rescued in TonEBP haploinsufficiency mice. Altogether, our results demonstrate an intracellular machinery within hypothalamic AVP cells that is responsible for dehydration-induced AVP synthesis.

    View details for DOI 10.3389/fendo.2021.627343

    View details for Web of Science ID 000634825800001

    View details for PubMedID 33796071

    View details for PubMedCentralID PMC8008816

  • Function of astrocyte MyD88 in high-fat-diet-induced hypothalamic inflammation JOURNAL OF NEUROINFLAMMATION Jin, S., Kim, K., Park, B., Kim, D., Jeong, B., Kang, D., Lee, T., Park, J., Kim, J., Lee, B. 2020; 17 (1): 195


    A growing body of evidence shows that hypothalamic inflammation is an important factor in the initiation of obesity. In particular, reactive gliosis accompanied by inflammatory responses in the hypothalamus are pivotal cellular events that elicit metabolic abnormalities. In this study, we examined whether MyD88 signaling in hypothalamic astrocytes controls reactive gliosis and inflammatory responses, thereby contributing to the pathogenesis of obesity.To analyze the role of astrocyte MyD88 in obesity pathogenesis, we used astrocyte-specific Myd88 knockout (KO) mice fed a high-fat diet (HFD) for 16 weeks or injected with saturated free fatty acids. Astrocyte-specific gene expression in the hypothalamus was determined using real-time PCR with mRNA purified by the Ribo-Tag system. Immunohistochemistry was used to detect the expression of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, phosphorylated signal transducer and activator of transcription 3, and α-melanocyte-stimulating hormone in the hypothalamus. Animals' energy expenditure was measured using an indirect calorimetry system.The astrocyte-specific Myd88 KO mice displayed ameliorated hypothalamic reactive gliosis and inflammation induced by injections of saturated free fatty acids and a long-term HFD. Accordingly, the KO mice were resistant to long-term HFD-induced obesity and showed an improvement in HFD-induced leptin resistance.These results suggest that MyD88 in hypothalamic astrocytes is a critical molecular unit for obesity pathogenesis that acts by mediating HFD signals for reactive gliosis and inflammation.

    View details for DOI 10.1186/s12974-020-01846-w

    View details for Web of Science ID 000544000800002

    View details for PubMedID 32560726

    View details for PubMedCentralID PMC7304177

  • Brain-specific chemokine FAM19A5 induces hypothalamic inflammation. Biochemical and biophysical research communications Kang, D., Kim, H. R., Kim, K. K., Kim, D. H., Jeong, B., Jin, S., Park, J. W., Seong, J. Y., Lee, B. J. 2020


    The cytokine-like protein FAM19A5 is highly expressed in the brain, but little is known about its functions there. Here, we found that FAM19A5 was expressed in mouse hypothalamic cells expressing proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related peptide (AgRP), and in the microglia. Tumor necrosis factor-alpha (TNF-alpha), which induces inflammatory sickness responses, greatly increased hypothalamic expression of FAM19A5. Knockdown of FAM19A5 expression resulted in decreased TNF-alpha-induced anorexia, body weight loss and TNF-alpha-induced expression of inflammatory factors. In contrast, intracerebroventricular administration of FAM19A5 induced anorexia, body weight loss and hyperthermia, together with increased expression of inflammatory factors. FAM19A5 injection also induced increases in c-fos activation and POMC mRNA level in hypothalamic POMC neurons. Together, these results suggest that FAM19A5 plays an important role in hypothalamic inflammatory responses.

    View details for DOI 10.1016/j.bbrc.2019.12.119

    View details for PubMedID 31954515

  • Tonicity-responsive enhancer binding protein (TonEBP) regulates TNF-α-induced hypothalamic inflammation. FEBS letters Kim, H. R., Kim, D. H., Kim, K. K., Jeong, B., Kang, D., Lee, T. H., Park, J. W., Kwon, H. M., Lee, B. J. 2019; 593 (19): 2762-2770


    Tonicity-responsive enhancer binding protein (TonEBP) is a widely expressed transcription factor and is important in the regulation of inflammatory cytokines. Here, we have identified TonEBP expression in the hypothalamus, which is particularly high in proopiomelanocortin (POMC) neurons. TonEBP overexpression stimulates POMC transcription, and TonEBP haploinsufficiency in TonEBP (+/-) mice results in a decrease in hypothalamic POMC expression. TonEBP (+/-) mice show reduced sickness responses, which include anorexia and hyperthermia, that are initially induced by tumor necrosis factor (TNF)-α. TonEBP (+/-) mice also show lower levels of TNF-α-induced hypothalamic expression of POMC and pro-inflammatory cytokines. These results suggest that TonEBP is an important molecular regulator in the development of inflammatory sickness responses through the control of POMC and pro-inflammatory cytokine expression in the hypothalamus.

    View details for DOI 10.1002/1873-3468.13533

    View details for PubMedID 31281956

  • NELL2 Function in the Protection of Cells against Endoplasmic Reticulum Stress MOLECULES AND CELLS Kim, D., Kim, H., Kim, K., Park, J., Lee, B. 2015; 38 (2): 145-150


    Continuous intra- and extracellular stresses induce disorder of Ca(2+) homeostasis and accumulation of unfolded protein in the endoplasmic reticulum (ER), which results in ER stress. Severe long-term ER stress triggers apoptosis signaling pathways, resulting in cell death. Neural epidermal growth factor-like like protein 2 (NELL2) has been reported to be important in protection of cells from cell death-inducing environments. In this study, we investigated the cytoprotective effect of NELL2 in the context of ER stress induced by thapsigargin, a strong ER stress inducer, in Cos7 cells. Overexpression of NELL2 prevented ER stress-mediated apoptosis by decreasing expression of ER stress-induced C/EBP homologous protein (CHOP) and increasing ER chaperones. In this context, expression of anti-apoptotic Bcl-xL was increased by NELL2, whereas NELL2 decreased expression of pro-apoptotic proteins, such as cleaved caspases 3 and 7. This anti-apoptotic effect of NELL2 is likely mediated by extracellular signal-regulated kinase (ERK) signaling, because its inhibitor, U0126, inhibited effects of NELL2 on the expression of anti- and pro-apoptotic proteins and on the protection from ER stress-induced cell death.

    View details for DOI 10.14348/molcells.2015.2216

    View details for Web of Science ID 000352448100007

    View details for PubMedID 25537860

    View details for PubMedCentralID PMC4332037

  • Neural Epidermal Growth Factor-Like Like Protein 2 (NELL2) Promotes Aggregation of Embryonic Carcinoma P19 Cells by Inducing N-Cadherin Expression PLOS ONE Kim, D., Kim, H., Choi, E., Kim, D., Kim, K., Kim, B., Park, J., Lee, B. 2014; 9 (1): e85898


    NELL2 was first identified as a mammalian homolog of chick NEL (Neural EGF-like) protein. It is almost exclusively expressed in neurons of the rat brain and has been suggested to play a role in neural differentiation. However, there is still no clear evidence for the detailed function of NELL2 in the differentiation of neurons. In this study, we identified NELL2 function during neural differentiation of mouse embryonic carcinoma P19 cells. Endogenous expression of NELL2 in the P19 cells increased in parallel with the neuronal differentiation induced by retinoic acid (RA). We found that the mouse NELL2 promoter contains RA response elements (RAREs) and that treatment with RA increased NELL2 promoter activity. Transfection of P19 cells with NELL2 expression vectors induced a dramatic increase in cell aggregation, resulting in the facilitation of neural differentiation. Moreover, NELL2 significantly increased N-cadherin expression in the P19 cell. These data suggest that NELL2 plays an important role in the regulation of neuronal differentiation via control of N-cadherin expression and cell aggregation.

    View details for DOI 10.1371/journal.pone.0085898

    View details for Web of Science ID 000330244500137

    View details for PubMedID 24465772

    View details for PubMedCentralID PMC3897553

  • Herpes Virus Entry Mediator Signaling in the Brain Is Imperative in Acute Inflammation-Induced Anorexia and Body Weight Loss ENDOCRINOLOGY AND METABOLISM Kim, K., Jin, S., Lee, B. 2013; 28 (3): 214-220


    Reduced appetite and body weight loss are typical symptoms of inflammatory diseases. A number of inflammatory stimuli are responsible for the imbalance in energy homeostasis, leading to metabolic disorders. The herpes virus entry mediator (HVEM) protein plays an important role in the development of various inflammatory diseases, such as intestinal inflammation and diet-induced obesity. However, the role of HVEM in the brain is largely unknown. This study aims to investigate whether HVEM signaling in the brain is involved in inflammation-induced anorexia and body weight loss.Food intake and body weight were measured at 24 hours after intraperitoneal injection of lipopolysaccharide (LPS) or intracerebroventricular injection of recombinant mouse LIGHT (also called tumor necrosis factor receptor superfamily 14, TNFSF14), an HVEM ligand, into 8- to 10-week-old male C57BL/6 mice and mice lacking HVEM expression (HVEM-/-). We also assessed LPS-induced change in hypothalamic expression of HVEM using immunohistochemistry.Administration of LPS significantly reduced food intake and body weight, and moreover, increased expression of HVEM in the hypothalamic arcuate nucleus. However, LPS induced only minor decreases in food intake and body weight in HVEM-/- mice. Administration of LIGHT into the brain was very effective at decreasing food intake and body weight in wild-type mice, but was less effective in HVEM-/- mice.Activation of brain HVEM signaling is responsible for inflammation-induced anorexia and body weight loss.

    View details for DOI 10.3803/EnM.2013.28.3.214

    View details for Web of Science ID 000409622100009

    View details for PubMedID 24396681

    View details for PubMedCentralID PMC3811702