RESEARCH

We study obesity, metabolic syndromes, and chronic liver disease, focusing on neurocircuits, liver health and disease, and fat biology (white, brown, and beige fat).

Brain Control of Body Weight and Metabolism

• SH2B1 neurocircuits govern energy balance, body weight, and metabolism. We found that global or LepRb neuron-specific deletion of Sh2b1 results in leptin resistance, BDNF resistance, obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) in mice. Likewise, human SH2B1 mutations are also associated with obesity and metabolic syndromes. We mapped a PVHSH2B1→DRN circuit governing food intake and energy expenditure. At the molecular level, SH2B1 directly binds to JAK2 and enhances leptin signaling. SH2B1 also binds to TrkB to promote BDNF signaling. SH2B1 displays extensive posttranslational modifications, including phosphorylation and methylation. Our goal is to 1) map SH2B1 neurocircuits, 2) delineate how human SH2B1 mutations cause obesity, and 3) elucidate how SH2B1 modifications shape the ability of SH2B1 neurocircuits to control food intake, energy expenditure, body weight, and metabolism.

• Slug-based epigenetic reprogramming of hypothalamic neurocircuits promotes leptin resistance, obesity, and metabolic syndromes. Transcriptional regulator Slug, also known as SNAI2, can either activate or repress gene transcription by recruiting transcriptionally active or repressive epigenetic modifiers, respectively. We demonstrated that deletion of Snai2 in LepRb neurons attenuates, whereas hypothalamus-specific overexpression of Slug augments, obesity, type 2 diabetes, and MASLD. Our goal is to 1) define Slug neurocircuits, 2) identify Slug-associated epigenetic modifiers and Slug target genes, 3) elucidate Slug-elicited epigenetic memory (histone modifications) shaping Slug neurocircuit activity, and 4) develop an epigenetic strategy to combat obesity.

• m6A-based epitranscriptomic reprogramming of hypothalamic neurocircuits influences obesity pathogenesis. RNA modifications pivotally regulate RNA metabolism, protein synthesis, and proteostasis, thereby controlling cell proliferation, differentiation, and function. We observed that obesity is associated with considerable alterations in RNA N6-methyladenosine (m6A) modification as well as expression of m6A-dependent RNA-binding proteins (m6A readers) in the hypothalamus. Our goal is to 1) delineate how m6A writers (METTL3/14 RNA methyltransferases) and m6A readers (YTHDC1, YTHDF1-3) regulate the development and function of hypothalamic neurocircuits in the setting of obesity, and 2) identify m6A target transcripts linking m6A-based epitranscriptomic remodeling to energy imbalance, obesity, and metabolic syndromes.

Liver Metabolism, Homeostasis, and Disease

• TRAF2, TRAF3, and NIK link liver inflammation to type 2 diabetes and MASLD. TRAF2 and TRAF3 function both as adaptor proteins and as ubiquitin E3 ligases to mediate inflammatory pathways. TRAF2, TRAF3, and cIAP1/2 (E3 ligases) assemble into a ubiquitin E3 ligase complex that mediates ubiquitination and degradation of NF-κB-inducing kinase (NIK). NIK, also known as MAP3K14, is required for the noncanonical NF-κB pathway. We noticed that liver TRAF2, TRAF3, and NIK are upregulated in obesity. They in turn promote gluconeogenesis and diabetes progression by enhancing glucagon responses. Liver TRAF3 and NIK also promote MASLD by increasing hepatic de novo lipogenesis. We aim to establish individual TRAF2, TRAF3, and NIK cascades and delineate how these signaling events link liver local microenvironments to hepatic metabolism and pathogeneses of type 2 diabetes and MASLD.

• NIK and TRAF2 bridge inflammation and hepatocellular stress to liver injury, regeneration, and fibrosis. We found that hepatic NIK is markedly upregulated in response to metabolic stress, oxidative stress, and hepatotoxin exposure. Aberrant NIK suppresses hepatocyte replication, thus impairing liver regeneration. Additionally, NIK enhances secretion of hepatokines that activate Kupffer cells/macrophages. Kupffer cell/macrophage-released mediators in turn induce hepatocyte injury/death, leading to liver injury, inflammation, and fibrosis. Hepatic TRAF2 also profoundly influences liver injury, regeneration, and fibrosis. Our goal is to elucidate how hepatic TRAF2 and NIK pathways act in concert to regulate liver cell crosstalk, liver injury, regeneration, and fibrosis in chronic liver disease.

• Biliary NIK promotes ductular reaction (cholangiocyte expansion) and cholestatic liver disease. We revealed that biliary NIK is dramatically upregulated in cholestatic liver injury. NIK cell-autonomously increases cholangiocyte proliferation while suppressing cholangiocyte death. Cholangiocyte-specific ablation of NIK prevents ductular reaction, liver injury, and fibrosis in mouse models of cholestatic liver injury. We aim to elucidate biliary NIK signaling cascades and delineate how they promote ductular reaction and biliary liver disease.

• Slug-based epigenetic reprogramming promotes MASLD. We reported that hepatic Slug is substantially upregulated in obesity. Hepatocyte-specific deletion of Slug prevents diet-induced MASLD; conversely, liver-specific overexpression of Slug, but not epigenetic-defective Slug mutants, induces MASLD. Additionally, hepatic Slug acts in concert with related Snai1 to promote liver regeneration. Using Slug and Snai1 as a molecular model, we aim to elucidate epigenetic mechanisms (e.g. histone modifications) guiding liver metabolism, integrity, and regeneration.

• Role of RNA m6A modification and RNA-binding proteins in MASLD. We noticed that obesity is associated with marked alterations in RNA m6A levels and expression of m6A writers and m6A readers in the liver. Hepatocyte-specific ablation of m6A writers or m6A readers disrupts liver metabolic processes and liver homeostasis. We aim to delineate how individual m6A writers (METTL3/14) and m6A readers (YTHDC1, YTHDF1-3) regulate liver metabolism, injury, regeneration, and fibrosis.

• TRAF2 and NIK regulate evolutions of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Given that hepatic TRAF2 and NIK profoundly influence liver injury, inflammation, regeneration, and fibrosis (risk factors for HCC and iCCA), we aim to delineate how hepatobiliary TRAF2 and NIK pathways regulate HCC and iCCA tumorigenesis, tumor microenvironments, and the metabolic response of the host to liver tumors.

White, Brown, and Beige Fat Biology

• The sympathetic nerve inputs critically stimulate brown and beige fat growth and activation. We showed that LepRb neuron-specific deletion of Sh2b1 abolishes the ability of leptin to increase sympathetic nerve outflows into brown adipose tissue (BAT), leading to BAT and beige fat dysfunctions. Using these mouse models, we investigate neuronal and hormonal regulation of adipose stem cells, adipogenesis, and white, brown, beige fat growth.

• Epigenetic and epitranscriptomic regulation of lipolysis and lipid trafficking. Adipose lipolysis mobilizes free fatty acids to meet metabolic demands. However, excessive lipolysis induces aberrant lipid trafficking from fat to the liver, promoting MASLD. We found that Snai1 represses ATGL transcription by an epigenetic mechanism in adipose tissues, thus inhibiting lipolysis. We observed that METTL14 installs m6A onto ATGL transcripts, thereby inhibiting ATGL translation and lipolysis. The METTL14/m6A pathway also inhibits β adrenergic signaling, further inhibiting lipolysis. Based on these findings, we aim to define an epigenetic paradigm and an m6A-based epitranscriptomic paradigm guiding adipose lipolysis, lipid trafficking, and ectopic lipotoxicity (e.g., MASLD).

Crosstalk between Fat, Liver, and Brain

• BAT protection against alcohol-related liver disease (ALD) and metabolic dysfunction and ALD (MetALD)―BAT/Liver crosstalk. We noticed that alcohol consumption profoundly stimulates, via the sympathetic nervous system, activation of brown adipose tissue (BAT) and beige fat. BAT and beige fat in turn counteract liver steatosis, injury, inflammation, and fibrosis. In addition to oxidizing toxic free fatty acids, brown and beige adipocytes also secrete hepatoprotective mediators (adipokines). We aim to identify and characterize the mediators in ALD and MetALD.

• Adipose hormones regulate, via hypothalamic neurocircuits, body weight and metabolism ―Fat/Brain crosstalk. We found that adipose epigenetic and epitranscriptomic reprogramming influence energy balance, body weight, and metabolism at least in part by releasing adipose hormones that act on hypothalamic neurocircuits. Our goal is to identify those hormones and delineate how they shape hypothalamic neurocircuit activity.

• Hepatic hormones regulate body weight and metabolism through hypothalamic neurocircuits―Liver/Brain crosstalk. We observed that liver inflammatory, epigenetic, and epitranscriptomic pathways regulate secretion of mediators (hepatokines) that act on hypothalamic neurocircuits to influence energy balance, body weight, and metabolism. We identified hepatokines MUP1 and lipocalin-13 that regulate glucose metabolism. We aim to identify novel mediators (secreted by hepatocytes and/or cholangiocytes) that act on hypothalamic neurocircuits to regulate energy balance, body weight, and metabolism.