Reduced intestinal lipid absorption and body weight-independent improvements in insulin sensitivity in high-fat diet-fed Park2 knockout mice

Abstract

Shulman GI, Jurczak MJ. Reduced intestinal lipid absorption and body weight-independent improvements in insulin sensitivity in high-fat diet-fed Park2 knockout mice. Am J Physiol Endocrinol Metab 311: E105-E116, 2016. First published May 10, 2016; doi:10.1152/ajpendo.00042.2016.-Mitochondrial dysfunction is associated with many human diseases and results from mismatch of damage and repair over the life of the organelle. PARK2 is a ubiquitin E3 ligase that regulates mitophagy, a repair mechanism that selectively degrades damaged mitochondria. Deletion of PARK2 in multiple in vivo models results in susceptibility to stress-induced mitochondrial and cellular dysfunction. Surprisingly, Park2 knockout (KO) mice are protected from nutritional stress and do not develop obesity, hepatic steatosis or insulin resistance when fed a high-fat diet (HFD). However, these phenomena are casually related and the physiological basis for this phenotype is unknown. We therefore undertook a series of acute HFD studies to more completely understand the physiology of Park2 KO during nutritional stress. We find that intestinal lipid absorption is impaired in Park2 KO mice as evidenced by increased fecal lipids and reduced plasma triglycerides after intragastric fat challenge. Park2 KO mice developed hepatic steatosis in response to intravenous lipid infusion as well as during incubation of primary hepatocytes with fatty acids, suggesting that hepatic protection from nutritional stress was secondary to changes in energy balance due to altered intestinal triglyceride absorption. Park2 KO mice showed reduced adiposity after 1-wk HFD, as well as improved hepatic and peripheral insulin sensitivity. These studies suggest that changes in intestinal lipid absorption may play a primary role in protection from nutritional stress in Park2 KO mice by preventing HFD-induced weight gain and highlight the need for tissue-specific models to address the role of PARK2 during metabolic stress. lipid absorption; mitophagy; PARK2; insulin resistance; liver; small intestine; obesity PARK2 IS A UBIQUITIN E3 LIGASE that was first identified in patients with autosomal recessive juvenile Parkinsonism (ARJP) and has since emerged as one of the most frequently mutated genes in this disorder (25,31). PARK2 is comprised of an NH 2 -terminal ubiquitin-like domain, a novel PARK2-specific domain, and two RING-finger domains separated by an inbetween RING-finger (IBR) domain in the COOH terminus (25, 32). PARK2 mutations resulting in ARJP typically lead to loss of E3 ligase activity and commonly occur within the COOH-terminal RING-finger or IBR domains (9). PARK2 acts as a multifunctional E3 ligase in that it cooperates with several E2 conjugating enzymes, such as UBCH7, UBCH8, and UBCH13/UEV1, and catalyzes mono-and polyubiquitination with Lys 48 and Lys 63 linkages, indicating proteasome-dependent and -independent effects of PARK2-mediated ubiquitination (9,11,17,41,53). Multiple PARK2 substrates have been reported, but it still remains unclear how loss of PARK2 E3 li...

A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses

“…Whole body siRNA of NTSC2 in mice showed increased lipolysis [ 13 ] and VTI1A was shown to interact with GLUT4 in adipocytes in mice[ 14 ]. More directly, PARK2 KO mice show decreased fat absorption and are leaner on high-fat diets[ 15 ]. VASP KO mice have reduced body weight and increased brown adipocytes[ 16 ].…”

Role and Mechanisms of Mitophagy in Liver Diseases

“…Further mechanical studies implied that Parkin conferred these effects via ubiquitin-mediated stabilization of the lipid transporter CD36 in the liver [141,142]. Interestingly, in an acute HFD feeding model, impaired intestinal lipid absorption was found in Parkin knockout mice as evidenced by increased fecal lipids and reduced plasma triglycerides after intragastric fat challenge, while intravenous lipid infusion can cause liver steatosis in the knockout mice [143]. These results highlight the essential role of Parkin in regulating lipid absorption besides mediating mitophagy, which may contribute to the contrary effects of Parkin deficiency in alcohol and HFD-induced liver injury.…”

Hepatic insulin sensitivity is improved in high‐fat diet‐fed Park2 knockout mice in association with increased hepatic AMPK activation and reduced steatosis

“…Not surprisingly, HFD‐fed Park2 KO mice displayed improved glucose and insulin tolerance when compared with obese HFD‐fed wild‐type (WT) mice, but it was unclear whether changes in liver fat and glucose homeostasis after HFD feeding were due to loss of Park2 or secondary to the protection from obesity (Kim et al, ). To address this question, we fed Park2 KO mice a short‐term, one‐week HFD in order to induce hepatic insulin resistance without major changes in body weight (Costa et al, ). Under these conditions, body fat was modestly reduced by 1.2 g or 5% in Park2 KO mice, but there was no difference in body weight.…”

“…Under these conditions, body fat was modestly reduced by 1.2 g or 5% in Park2 KO mice, but there was no difference in body weight. Hepatic insulin sensitivity, as assessed by hyperinsulinemic euglycemic clamp, was markedly improved in Park2 KO mice; whereas hyperinsulinemia produced only a 40% reduction in hepatic glucose production in HFD‐fed WT mice, hepatic glucose production was almost completely suppressed (~97%) by insulin in HFD‐fed Park2 KO mice (Costa et al, ). These data demonstrated that Park2 KO mice were protected against diet‐induced hepatic insulin resistance independent of changes in body weight, but the underlying mechanism was not addressed.…”