Hui-Young Lee

Ectopic lipid accumulation is a core contributor to insulin resistance and metabolic diseases, including type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Conventional therapies have primarily focused on redistributing lipid burden across tissues or modulating specific pathways. However, this often causes compensatory responses that merely shift the burden rather than resolve the underlying lipid excess. In this review, we introduce the concept of the ballooning effect, wherein single-target interventions inadvertently exacerbate lipid accumulation in non-target tissues. We then explore fundamental strategies for true lipid disposal, which aim either to prevent lipid influx or to promote complete lipid oxidation. Among these, mild mitochondrial uncoupling emerges as a promising solution. By dissipating substrate energy as heat, mitochondrial uncoupling reduces ectopic lipid burden without relying on redistribution. Recent advances have yielded safer chemical uncouplers and novel endogenous protein-based mechanisms that enable controlled uncoupling with minimal toxicity. Together, these provide a new framework for next-generation metabolic therapies that move beyond lipid redistribution and aim for a true lipid disposal, potentially offering a safe and effective strategy.

Background: Maintaining skeletal muscle mass and strength is crucial to prevent sarcopenia during healthy ageing. Ankyrin repeat and suppressor of cytokine signalling box protein 2 (Asb2), an E3 ligase, has been implicated in regulating muscle mass; however, its roles on muscle strength remain unclear, with mixed findings from previous studies. Overexpression of Asb2 decreases muscle mass, whereas its knockdown delays myoblast differentiation and reduces contractile proteins. Given these contradictory findings, we aimed to clarify the role of Asb2 in muscle mass and strength using a skeletal muscle‐specific Asb2 knockout (Asb2 MKO) mouse model. Additionally, we investigate the long‐term effects of Asb2 on aged muscle, underlying mechanisms on muscle regulation and metabolic effects of Asb2 MKO mice to better understand its role in muscle function and age‐related metabolic diseases.Methods: Asb2 MKO mice were generated using Acta1‐Cre recombinase. Body composition was quantified in male and female mice up to 18 months of age. Muscle strength, energy expenditure and glucose metabolism were evaluated using the grip strength test, mitochondrial oxygen consumption measurement, indirect calorimetry and glucose/insulin tolerance tests. Transcriptomic analyses and siRNA studies were performed to elucidate the mechanisms underlying the Asb2 deletion.Results: The MKO mice were born healthy and exhibited selective Asb2 deletion in the skeletal muscle, leaving the cardiac muscle unaffected. This deletion led to an increase in the mass of various skeletal muscles (9%–23%, p < 0.05) and improved grip strength (~10%, p < 0.05), both of which were sustained throughout the ageing process. The MKO mice also revealed enhanced mitochondrial function, energy expenditure and whole‐body insulin sensitivity. Transcriptomic data supported the muscle phenotype observed in the MKO mice. Notably, desmin, a protein critical for structural integrity and mitochondrial function, was identified as a target protein of the ASB2 E3 ligase.Conclusions: Skeletal muscle‐specific deletion of Asb2 led to increased muscle mass and strength, potentially through preservation of desmin levels. These findings suggest that targeting Asb2 may enhance muscle growth and prevent age‐related muscle decline, with potential benefits for metabolic health, particularly by improving mitochondrial function and insulin sensitivity.

Hepatic endoplasmic reticulum (ER) stress is implicated in the development of steatosis and its progression to nonalcoholic steatohepatitis (NASH). The ER in the liver can sustain metabolic function by activating defense mechanisms that delay or prevent the progression of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanisms by which the ER stress response protects against NAFLD remain largely unknown. Recently, activin E has been linked to metabolic diseases such as insulin resistance and NAFLD. However, the physiological conditions and regulatory mechanisms driving hepatic Inhbe expression (which encodes activin E) as well as the metabolic role of activin E in NAFLD require further investigation. Here we found that hepatic Inhbe expression increased under prolonged fasting and ER stress conditions, which was mediated by ATF4, as determined by promoter analysis in a mouse model. Consistently, a positive correlation between INHBE and ATF4 expression levels in relation to NAFLD status was confirmed using public human NAFLD datasets. To investigate the role of activin E in hepatic steatosis, we assessed the fluxes of the lipid metabolism in an Inhbe-knockout mouse model. These mice displayed a lean phenotype but developed severe hepatic steatosis under a high-fat diet. The deficiency of Inhbe resulted in increased lipolysis in adipose tissue, leading to increased fatty acid influx into the liver. Conversely, hepatic overexpression of Inhbe ameliorated hepatic steatosis by suppressing lipolysis in adipose tissue through ALK7–Smad signaling. In conclusion, activin E serves as a regulatory hepatokine that prevents fatty acid influx into the liver, thereby protecting against NAFLD.

Tryptophan is an essential amino acid that is metabolized in the intestine by gut bacteria into indole derivatives, including tryptamine. However, little is known about which bacterial tryptophan metabolites directly influence obesity. In this study, we identified tryptamine as a bacterial metabolite that significantly reduced fat mass following the intraperitoneal injection of five bacterial tryptophan end-products in a diet-induced obese mouse model. Interestingly, tryptamine, a serotonin analog, inhibited both lipogenesis and lipolysis in adipose tissue, which was further confirmed in a 3T3-L1 adipocyte cell culture study. Moreover, oral tryptamine supplementation markedly reduced fat mass and improved insulin sensitivity in a long-term, high-fat-diet, pair-feeding model. These studies demonstrate the therapeutic potential of tryptamine, a bacterial tryptophan metabolite, in ameliorating obesity and insulin resistance by directly regulating lipogenesis and lipolysis in white adipose tissue.

Graphislactone A (GPA), a secondary metabolite derived from a mycobiont found in the lichens of the genus Graphis, exhibits antioxidant properties. However, the potential biological functions and therapeutic applications of GPA at the cellular and animal levels have not yet been investigated. In the present study, we explored the therapeutic potential of GPA in mitigating non-alcoholic fatty liver disease (NAFLD) and its underlying mechanisms through a series of experiments using various cell lines and animal models. GPA demonstrated antioxidant capacity on a par with that of vitamin C in cultured hepatocytes and reduced the inflammatory response induced by lipopolysaccharide in primary macrophages. However, in animal studies using an NAFLD mouse model, GPA had a milder impact on liver inflammation while markedly attenuating hepatic steatosis. This effect was confirmed in an animal model of early fatty liver disease without inflammation. Mechanistically, GPA inhibited lipogenesis rather than fat oxidation in cultured hepatocytes. Similarly, RNA sequencing data revealed intriguing associations between GPA and the adipogenic pathways during adipocyte differentiation. GPA effectively reduced lipid accumulation and suppressed lipogenic gene expression in AML12 hepatocytes and 3T3-L1 adipocytes. In summary, our study demonstrates the potential application of GPA to protect against hepatic steatosis in vivo and suggests a novel role for GPA as an underlying mechanism in lipogenesis, paving the way for future exploration of its therapeutic potential.

Single-nucleotide polymorphisms in the human juxtaposed with another zinc finger protein 1 ( JAZF1 ) gene have repeatedly been associated with both type 2 diabetes (T2D) and height in multiple genome-wide association studies (GWAS); however, the mechanism by which JAZF1 causes these traits is not yet known. To investigate the possible functional role of JAZF1 in growth and glucose metabolism in vivo, we generated Jazf1 knockout (KO) mice and examined body composition and insulin sensitivity both in young and adult mice by using ¹ H-nuclear magnetic resonance and hyperinsulinemic-euglycemic clamp techniques. Plasma concentrations of insulin-like growth factor 1 (IGF-1) were reduced in both young and adult Jazf1 KO mice, and young Jazf1 KO mice were shorter in stature than age-matched wild-type mice. Young Jazf1 KO mice manifested reduced fat mass, whereas adult Jazf1 KO mice manifested increased fat mass and reductions in lean body mass associated with increased plasma growth hormone (GH) concentrations. Adult Jazf1 KO manifested muscle insulin resistance that was further exacerbated by high-fat diet feeding. Gene set enrichment analysis in Jazf1 KO liver identified the hepatocyte hepatic nuclear factor 4 alpha (HNF4α), which was decreased in Jazf1 KO liver and in JAZF1 knockdown cells. Moreover, GH-induced IGF-1 expression was inhibited by JAZF1 knockdown in human hepatocytes. Taken together these results demonstrate that reduction of JAZF1 leads to early growth retardation and late onset insulin resistance in vivo which may be mediated through alterations in the GH-IGF-1 axis and HNF4α.

Mechanisms linking gut microbial metabolites to insulin resistance

Liver fibrosis is a consequence of chronic liver injury associated with chronic viral infection, alcohol abuse, and nonalcoholic fatty liver. The evidence from clinical and animal studies indicates that transforming growth factor-β (TGF-β) signaling is associated with the development of liver fibrosis. Krüppel-like factor 10 (KLF10) is a transcription factor that plays a significant role in TGF-β-mediated cell growth, apoptosis, and differentiation. In recent studies, it has been reported to be associated with glucose homeostasis and insulin resistance. In the present study, we investigated the role of KLF10 in the progression of liver disease upon a high-sucrose diet (HSD) in mice. Wild type (WT) and Klf10 knockout (KO) mice were fed either a control chow diet or HSD (50% sucrose) for eight weeks. Klf10 KO mice exhibited significant hepatic steatosis, inflammation, and liver injury upon HSD feeding, whereas the WT mice exhibited mild hepatic steatosis with no apparent liver injury. The livers of HSD-fed Klf10 KO mice demonstrated significantly increased endoplasmic reticulum stress, oxidative stress, and proinflammatory cytokines. Klf10 deletion led to the development of sucrose-induced hepatocyte cell death both in vivo and in vitro. Moreover, it significantly increased fibrogenic gene expression and collagen accumulation in the liver. Increased liver fibrosis was accompanied by increased phosphorylation and nuclear localization of Smad3. Here, we demonstrate that HSD-fed mice develop a severe liver injury in the absence of KLF10 due to the hyperactivation of the endoplasmic reticulum stress response and CCAAT/enhance-binding protein homologous protein (CHOP)-mediated apoptosis of hepatocytes. The current study suggests that KLF10 plays a protective role against the progression of hepatic steatosis into liver fibrosis in a lipogenic state.

Lee Y, et al. Diabetes Metab J. 2020 Jan;44:e34. https://doi.org/10.4093/dmj.2019.0220

Skeletal muscle is a major organ for glucose disposal and thermogenesis. While hepatic fructose-1,6-bisphosphatase is well known as a key enzyme for gluconeogenesis, the role of muscle fructose-1,6-bisphosphatase 2 (Fbp2) in glucose disposal and thermogenesis is unknown. Here, using Fbp2 knockout (KO) mice, we assessed the physiological role of Fbp2 in energy and glucose metabolism and thermogenesis. In vivo assessments of energy metabolism, glucose metabolism, and thermogenesis were performed by indirect calorimetry, hyperinsulinemic-euglycemic clamp, and cold challenge studies, respectively. Under both feeding and fasting conditions, Fbp2 KO mice showed similar phenotypes regarding energy and glucose metabolism compared to wild-type (WT) mice. However, Fbp2 KO mice were severely intolerant to cold challenge under fasting conditions. Mechanistically, the cold-induced intramuscular conversion of lactate to glycogen (glyconeogenesis) is completely abolished in the KO muscle, which leads to a lack of glycogen source for thermogenesis in Fbp2 KO mice. The cold-intolerant phenotype of KO mice disappeared after feeding, and the KO mice were equally as cold tolerant as the WT mice and survived during the cold challenge for three weeks. Taken together, these data demonstrate that Fbp2 is essential for muscle thermogenesis by replenishing the intramuscular glycogen pool through glyconeogenesis when the exogenous glucose source is limited. These data imply the physiological importance of Fbp2 in thermal homeostasis and suggest a potential novel therapy targeted to increase glycogen replenishment upon cold stress.