Research by Andrew J. Lutkewitte, Ph.D.

Obesity affects over a billion people worldwide and has been identified as a leading risk factor for developing metabolic dysfunction-associated steatotic liver disease (MASLD), as well as insulin resistance (IR) and type two diabetes mellitus (T2DM). Paradoxically, the marked absence of adipose tissue (lipodystrophy) also leads to these comorbidities. This observation suggests that adipose tissue function directly regulates systemic metabolism rather than adipose tissue mass. Several studies in human patients have shown that pathophysiological adipose tissue (defined by adipose tissue insulin resistance, inflammation, and fibrosis) drives the development of hepatic diseases such as dyslipidemia, hepatic steatosis, metabolic dysfunction-associated steatohepatitis, and even fibrosis.

Our long-term goal is to understand the mechanistic basis by which adipose tissue crosstalk with the liver regulates hepatic metabolism. We have two current research projects ongoing. [1.] In adipocytes, triglycerides are generated through the glycerol-3-phosphate pathway. The penultimate step is the generation of diacylglycerol through the phosphatidic acid phosphohydrolase activity of lipin 1 (gene name Lpin1). We have shown that in humans, adipose, LPIN1 expression positively correlates with insulin sensitivity and negatively correlates to hepatic DNL. In line with this, we have generated mice lacking lipin 1 in adipose tissue, which display a lean yet metabolically unhealthy phenotype that includes hepatic steatosis and insulin resistance. Our ongoing research is to determine the mechanisms of these phenotypes. [2.] Although the liver maintains a unique ability to regenerate following injury or loss, this capacity is reduced in parallel with the severity of the MASLD disease progression. Therefore, understanding the underlying mechanisms that regulate hepatic regeneration in the context of obesity (a worsening pandemic) could provide novel insight into potential new therapies. We have developed two mouse models with dysfunctional adipocytes to understand the dynamic relationship between healthy adipose tissue and hepatic growth. We aim to assess how acute adipose tissue loss drives hepatic expansion and how this impacts the pathophysiology of the liver in response to increased lipid load.

Together, these studies will enhance our understanding of how adipose tissue and the liver communicate to establish metabolic equilibrium and could lead to innovative therapies for metabolic disorders.

Andrew J. Lutkewitte, Ph.D.
KC-MORE COBRE Research Project Leader
Assistant Professor, Endocrinology, Diabetes and Clinical Pharmacology
alutkewitte@kumc.edu