Research Projects

This year (2025), we celebrated the 104th anniversary of the discovery of insulin. Several research labs have spent the last century trying to understand how insulin works. All of us have seen tremendous progress, several breakthroughs, and developments in insulin, insulin receptor, and it signaling network research. However, we have not seen much of an improvement yet for diabetes, Metabolic dysfunction-associated steatohepatitis (MAFLD), suffering from insulin resistance, and also how does insulin resistance develop intrinsically? Altogether, even after 104 years of insulin discovery, the molecular underpinnings of insulin resistance remain a mystery. Animals affected by MAFLD, diabetes exhibit reductions in both the overall number of insulin receptors and the specific fraction found on cell membranes. Our recent study highlights the significance of E3 Ligase TRIM32 in controlling hepatic insulin receptor expression and signaling (Thakur et al.2025 EMBO reports, 1-19). Analysis of mouse liver and plasma revealed an inappropriate surge in TRIM32 expression among mice subjected to an HFD-induced MAFLD and human MASH livers. These findings suggest a direct sequence wherein the HFD instigates TRIM32 expression. This, in turn, governs INSR stability via direct ubiquitination, consequently diminishing insulin receptor expression. One of the key objectives of this project is to understand the precise mechanisms by which hepatic TRIM32 contributes to systemic insulin resistance, lipid metabolism, and gluconeogenesis. There is evidence from various genetically engineered mouse models that insulin resistance in one tissue can spread to other tissues, resulting in systemic insulin resistance. The mechanism of inter-tissue communication underlying the propagation of insulin resistance from one tissue to another is largely unknown. We hypothesized that diet-induced obesity dysregulates liver-to-adipose tissue communication (mediated by hepatokine; TRIM32) to promote systemic insulin resistance from the Liver to adipose tissue. In Aim 2, we will try to understand the precise mechanisms by which hepatic TRIM32 contributes to adipose tissue insulin resistance. In Aim 3, considering that plasma Trim32 concentrations are correlated with hepatic pathological features in the MASH mouse model, we propose developing a neutralizing antibody to interfere with systemic Trim32, which might be a promising therapeutic target for the treatment of systemic insulin resistance, obesity, and MAFLD. We describe below the specific aims derived from our preliminary data in support of this primary objective. Aim 1: Uncover molecular pathways by which TRIM32 regulates hepatic lipid metabolism and gluconeogenesis, and MAFLD. Here, we will investigate the effect of TRIM32 on lipid uptake, synthesis, oxidation, and export, as well as its role in regulating gluconeogenesis and insulin action. We will identify ubiquitination sites that lead to the degradation or internalization of INSR. Aim 2: Examine the impact of liver-secreted TRIM32 on insulin receptor signalling and lipid homeostasis in adipose tissue through liver-adipose tissue crosstalk. Using TRIM32 overexpressed (OE) stable cells and AAV8-TBG-trim32 mouse model, we will examine the following: a) elucidate the molecular mechanisms by which the hepatocyte-derived TRIM32 signaling exerts an endocrine effect to promote systemic insulin resistance, lipolysis in adipose tissue, b) investigate the mechanism by which TRIM32 is released from hepatocytes in HFD mice. These investigations aim to identify TRIM32 as a novel hepatokine that affects extrahepatic insulin sensitivity and metabolic homeostasis. Aim 3: Investigate the therapeutic potential of targeting TRIM32 for the treatment of hyperglycemia and hypertriglyceridemia in MAFLD. To achieve this aim, we propose generating neutralizing monoclonal antibodies against TRIM32 that can prevent insulin receptor downregulation in obesity and MAFLD