Dysfunctional adipose tissue's role in hepatic metabolic disease

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Excess adipose tissue (obesity) has been identified as a leading risk factor for developing fatty liver disease and type 2 diabetes. Paradoxically, the marked absence of adipose tissue (lipodystrophy) also leads to these comorbidities. These observations suggest that adipose function, not quantity, is critical for systemic metabolic regulation. The primary function of healthy adipose tissue is the regulated storage of lipids when nutrients are abundant and mobilization of free fatty acids and glycerol when nutrients are scarce, but dysfunction of these processes leads to ectopic lipid storage in the liver, which drives metabolic disease. Dogma suggests excessive free fatty acid export from visceral adipose dumps into the portal vein, overwhelming hepatic metabolism leading to hepatic steatosis. Obese patients have a reduced capacity to store fatty acids in adipose tissue and dysregulated lipolysis. However, recent studies suggest that ~40 % of hepatic lipids are derived by hepatic de novo lipogenesis (DNL), the conversion of carbohydrates to lipids within the liver. Hepatic DNL is regulated by the nutrient-sensing AMP Protein Kinase (AMPK), which suppresses the activity and expression of many DNL enzymes. The goal of this 3-year project is to establish the mechanistic links between adipose tissue dysfunction and dysregulated hepatic DNL. 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). Our preliminary data shows that in humans adipose, LPIN1 expression positively correlates with insulin sensitivity and negatively corelates 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. Importantly, these mice also have increased rates of hepatic DNL and expression of DNL enzymes that AMPK normally suppresses. Together these data suggest that inhibiting adipose tissue triglyceride synthesis activates de novo hepatic lipid synthesis from alternative carbon sources. We hypothesize that dysfunctional adipose tissue reduces hepatic nutrient sensing capacity through chronic AMPK inactivation driving DNL and hepatic steatosis. We also hypothesize that re-activation of hepatic AMPK will restore hepatic nutrient sensing serving to lower DNL and hepatic lipid storage. Because obesity is an acquired disease, we will use a model of adult-onset adipose dysfunction, an inducible adipose specific lipin 1 KO model. We will use comprehensive metabolic testing combined with phospho-proteomics to assess AMPK activation of hepatic DNL. We will overexpress constitutively active AMPK in livers of our adipose dysfunction models to rescue hepatic metabolism by suppressing DNL. We will also use multi-organ biopsies from the same patients undergoing abdominal surgery to confirm that LPIN1 expression inversely correlates with hepatic AMPK activation and identify additional novel molecular relationships between adipose tissue dysfunction and hepatic disease progression using a multi-omic approach.