Defects in hepatic lipid metabolism cause nonalcoholic fatty liver disease and insulin resistance, and these pathologies are closely linked. Regulation of lipid droplet metabolism is central to the control of intracellular fatty acid fluxes, and perilipin 5 (PLIN5) is important in this process. We examined the role of PLIN5 on hepatic lipid metabolism and systemic glycemic control using liver-specific Plin5-deficient mice (Plin5 LKO ). Hepatocytes isolated from Plin5 LKO mice exhibited marked changes in lipid metabolism characterized by decreased fatty acid uptake and storage, decreased fatty acid oxidation that was associated with reduced contact between lipid droplets and mitochondria, and reduced triglyceride secretion. With consumption of a high-fat diet, Plin5 LKO mice accumulated intrahepatic triglyceride, without significant changes in inflammation, ceramide or diglyceride contents, endoplasmic reticulum stress, or autophagy. Instead, livers of Plin5 LKO mice exhibited activation of c-Jun N-terminal kinase, impaired insulin signal transduction, and insulin resistance, which impaired systemic insulin action and glycemic control. Re-expression of Plin5 in the livers of Plin5 LKO mice reversed these effects. Together, we show that Plin5 is an important modulator of intrahepatic lipid metabolism and suggest that the increased Plin5 expression that occurs with overnutrition may play an important role in preventing hepatic insulin resistance.

ized by the onset of muscle weakness and loss of function usually in the late teens and with slow progression (2). Dysferlinopathies include limb-girdle muscular dystrophy type 2B and Miyoshi myopathy, with the proximal and distal limb-girdle muscles being the main muscles affected (2-4). Mouse models of dysferlinopathy harboring dysferlin deficiency or deletion (5-8) consistently have a late onset of dystropathology, by about 8 months of age, with pronounced replacement of myofibers by adipocytes (9). Dysferlin is a member of a large ferlin family of transmembrane proteins that are involved in protein vesicle trafficking and fusion (10), with dysferlin initially attracting attention due to its role in the resealing of experimentally damaged sarcolemma (11-13). Dysferlin is localized in intracellular membranes of skeletal muscles such as Ttubules and sarcoplasmic reticulum (14), plays a role in Ttubule formation (15), and appears to be involved in calcium homeostasis related to excitation-contraction coupling (16-18). Dysferlin is highly expressed in skeletal myofibers but is also present in many other tissues (19) and cells, including adipocytes (20), macrophages (21), and endothelium (22). Two striking features of human and mouse dysferlin-deficient muscles are the accumulation of many lipid droplets within myofibers and, at a later age, the apparent replacement of myofibers with extramyocellular adipocytes (9, 15). Histopathology is not evident in young mice aged 3 months but is pronounced by 8-12 months in some muscles, including psoas and quadriceps, with increasing severity by 19 months (23). Indeed, in older Dysf-deficient A/J mice, 20% to 40% of the myofibers in quadriceps and psoas muscles are replaced by adipocytes (15, 23). In humans, Abstract Defects in the gene coding for dysferlin, a membrane-associated protein, affect many tissues, including skeletal muscles, with a resultant myopathy called dysferlinopathy. Dysferlinopathy manifests postgrowth with a progressive loss of skeletal muscle function, early intramyocellular lipid accumulation, and a striking later replacement of selective muscles by adipocytes. To better understand the changes underpinning this disease, we assessed whole-body energy homeostasis, skeletal muscle fatty acid metabolism, lipolysis in adipose tissue, and the skeletal muscle lipidome using young adult dysferlin-deficient male BLAJ mice and age-matched C57Bl/6J WT mice. BLAJ mice had increased lean mass and reduced fat mass associated with increased physical activity and increased adipose tissue lipolysis. Skeletal muscle fatty acid metabolism was remodeled in BLAJ mice, characterized by a partitioning of fatty acids toward storage rather than oxidation. Lipidomic analysis identified marked changes in almost all lipid classes examined in the skeletal muscle of BLAJ mice, including sphingolipids, phospholipids, cholesterol, and most glycerolipids but, surprisingly, not triacylglycerol. These observations indicate that an early manifestation of dysferlin deficiency is the repro...

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Perilipin 5 (PLIN5) is a lipid-droplet-associated protein that coordinates intracellular lipolysis in highly oxidative tissues and is thought to regulate lipid metabolism in response to phosphorylation by protein kinase A (PKA). We sought to identify PKA phosphorylation sites in PLIN5 and assess their functional relevance in cultured cells and the livers of mice. We detected phosphorylation on S155 and identified S155 as a functionally important site for lipid metabolism. Expression of phosphorylation-defective PLIN5 S155A in Plin5 null cells resulted in decreased rates of lipolysis and triglyceride-derived fatty acid oxidation. FLIM-FRET analysis of protein-protein interactions showed that PLIN5 S155 phosphorylation regulates PLIN5 interaction with adipose triglyceride lipase at the lipid droplet, but not with α-β hydrolase domain-containing 5. Re-expression of PLIN5 S155A in the liver of Plin5 liver-specific null mice reduced lipolysis compared with wild-type PLIN5 re-expression, but was not associated with other changes in hepatic lipid metabolism. Furthermore, glycemic control was impaired in mice with expression of PLIN5 S155A compared with mice expressing PLIN5. Together, these studies demonstrate that PLIN5 S155 is required for PKA-mediated lipolysis and builds on the body of evidence demonstrating a critical role for PLIN5 in coordinating lipid and glucose metabolism.

Glucose-dependent insulinotropic polypeptide (GIP) is best known as an incretin hormone that is secreted from K-cells of the proximal intestine, but evidence also implicates a role for GIP in regulating lipid metabolism and adiposity. It is well established that GIP receptor knockout (GIPR KO) mice are resistant to diet-induced obesity; however, the factors mediating this effect remain unresolved. Accordingly, we aimed to elucidate the mechanisms leading to adiposity resistance in GIPR KO mice with a focus on whole-body energy balance and lipid metabolism in adipose tissues. Studies were conducted in age-matched male GIPR KO and wild type (WT) mice fed a high-fat diet for 10 weeks. GIPR KO mice gained less body weight and fat mass compared to WT littermates, and this was associated with increased energy expenditure but no differences in food intake or faecal energy loss. Upon an oral lipid challenge, fatty acid storage in inguinal adipose tissue was significantly increased in GIPR KO compared with WT mice. This was not related to differential expression of lipoprotein lipase in adipose tissue. Adipose tissue lipolysis was increased in GIPR KO compared with WT mice, particularly following b-adrenergic stimulation, and could explain why GIPR KO mice gain less adipose tissue despite increased rates of fatty acid storage in inguinal adipose tissue. Taken together, these results suggest that the GIPR is required for normal maintenance of body weight and adipose tissue mass by regulating energy expenditure and lipolysis.