Increased lipolysis and altered lipid homeostasis protect γ-synuclein–null mutant mice from diet-induced obesity

Abstract

Synucleins are a family of homologous proteins principally known for their involvement in neurodegeneration. γ-Synuclein is highly expressed in human white adipose tissue and increased in obesity.Here we show that γ-synuclein is nutritionally regulated in white adipose tissue whereas its loss partially protects mice from high-fat diet (HFD)-induced obesity and ameliorates some of the associated metabolic complications. Compared with HFD-fed WT mice, HFD-fed γ-synuclein-null mutant mice display increased lipolysis, lipid oxidation, and energy expenditure, and reduced adipocyte hypertrophy. Knockdown of γ-synuclein in adipocytes causes redistribution of the key lipolytic enzyme ATGL to lipid droplets and increases lipolysis. γ-Synuclein-deficient adipocytes also contain fewer SNARE complexes of a type involved in lipid droplet fusion. We hypothesize that γ-synuclein may deliver SNAP-23 to the SNARE complexes under lipogenic conditions. Via these independent but complementary roles, γ-synuclein may coordinately modulate lipid storage by influencing lipolysis and lipid droplet formation. Our data reveal γ-synuclein as a regulator of lipid handling in adipocytes, the function of which is particularly important in conditions of nutrient excess.U nderstanding the link between increased adiposity and the development of metabolic disease may reveal novel therapeutic targets to counter the rising pandemic of obesity. Inhibiting adipose tissue expansion alone is likely to worsen metabolic outcome, as evidenced by human syndromes of lipodystrophy, whereby inappropriately decreased adipose mass causes severe metabolic disorders (1). Indeed, adipose tissue dysfunction and/ or exceeded adipose storage capacity may underlie ectopic lipid accumulation and lipotoxicity in obesity (2). Therefore, a major challenge is to identify pathways via which adiposity can be reduced without concomitant increases in circulating lipids and attendant metabolic disease. Achieving this goal requires a better understanding of the molecular mechanisms that regulate lipid metabolism and storage in adipocytes, particularly in times of energy surplus.γ-Synuclein belongs to the synuclein family of proteins, whose founder member α-synuclein is best known for its links with neurodegenerative diseases, most notably Parkinson disease (3). To date, no clear cellular role is attributed to γ-synuclein, and ablation of γ-synuclein causes only minor changes in the nervous system (4-7). Recently, we and others have reported high levels of γ-synuclein expression in adipose tissue of humans and other mammals (8,9). Moreover, expression of γ-synuclein is increased in the adipose tissue of obese humans and decreased during caloric restriction (8).Here we demonstrate that γ-synuclein-null mice display significantly reduced adiposity and fewer metabolic derangements compared with WT mice following high-fat feeding. This appears to result from increased adipocyte lipolysis coupled to enhanced whole-body lipid oxidation and energy expenditure. At a molecular level, we i...

Plin2 Inhibits Cellular Glucose Uptake through Interactions with SNAP23, a SNARE Complex Protein

“…Moreover, increased partitioning of SNAP23 to cytosolic/microsomal compartments and reduced SNAP23 expression at the plasma membrane was also observed in studies using muscle cells of type-2 diabetic patients [69]. In keeping with this, it was recently demonstrated that α-synuclein null mice that are resistance to diet induced obesity showed decreased lipid droplet size because of reduced SNARE complex formation in adipocytes, further highlighting the role of SNARE proteins in lipid droplet formation and fusion [70]. It should be noted however, another report revealed FSP27 and Plin1 interact with each other and are involved in the formation of unilocular lipid droplets [66].…”

Loss of the liver X receptor LXRα/β in peripheral sensory neurons modifies energy expenditure

“…γ synuclein is a protein that modulates synaptic trafficking in neurons but also lipid droplets generating intracellular fatty acids. Notably, the γ synuclein whole body knockout is protected against diet-induced obesity (Oort et al, 2008; Millership et al, 2012).

10.7554/eLife.06667.009Figure 4.NG gene expression in LXRs Nav mice vs control mice.( A ) Gene expression in NG from LXRs Nav and control mice fed with NC or WD.

…”

Contrasting Effects of α-Synuclein and γ-Synuclein on the Phenotype of Cysteine String Protein α (CSPα) Null Mutant Mice Suggest Distinct Function of these Proteins in Neuronal Synapses

“…Outside the nervous system, this protein is abundant in white fat adipocytes, and the level of its expression correlates with the degree of obesity (36). Moreover, our latest study demonstrated the role of γ-synuclein in regulation of lipolysis and lipid droplet formation in adipocytes (37). In these cells, γ-synuclein is not associated with lipid droplets but potentiates translocation of cytosolic SNAP-23 to their surface, enhances triacylglyceride incorporation into lipid droplets, and increases their size at times of nutrient excess.…”