Role of the adipose PPARγ-adiponectin axis in susceptibility to stress and depression/anxiety-related behaviors

Abstract

Adaptive responses to stressful stimuli involving behavioral, emotional and metabolic changes are orchestrated by the nervous and endocrine systems. Adipose tissue has been recognized as a highly active metabolic and endocrine organ, secreting adipokines that operate as hormones to mediate the crosstalk with other organs including the brain. The role of adipose tissue in sensing and responding to emotional stress and in behavioral regulation, however, remains largely unknown. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a key transcriptional factor controlling adipokine gene expression. Here we show that chronic social defeat stress decreases mRNA and protein levels of PPARγ in adipose tissue of susceptible but not resilient mice, which was correlated with social avoidance behavior. A corresponding reduction in adipose adiponectin production was observed in susceptible mice. Rosiglitazone, a blood-brain barrier-impermeant PPARγ-selective agonist, elicited antidepressant- and anxiolytic-like behavioral effects in wild-type mice, with a concurrent increase in plasma adiponectin levels. These effects of rosiglitazone were absent in mice lacking adiponectin but having normal PPARγ expression in adipose tissue and brain. Moreover, pretreatment with the PPARγ-selective antagonist GW9662 blocked rosiglitazone-induced adiponectin expression and antidepressant/anxiolytic-like effects. Together, these results suggest that the behavioral responses to rosiglitazone are mediated through PPARγ-dependent induction of adiponectin. Our findings support an important role for the adipose PPARγ-adiponectin axis in susceptibility to stress and negative emotion-related behaviors. Selectively targeting PPARγ in adipose tissue may offer novel strategies for combating depression and anxiety.

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

“…Peroxisome proliferator‐activated receptor γ (PPARγ) is a ligand‐activated transcription factor that belongs to the nuclear receptor family and a master modulator of glucose and lipid metabolism, organelle differentiation, and inflammation (Guo et al., 2017; Zhao et al., 2016). These form heterodimers with the retinoid X receptor and bind to peroxisome proliferator response elements (PPREs) in the promoter region of respective target genes (Hallenborg et al., 2016).…”

“…Activation of PPARγ by troglitazone and pioglitazone reduces infarct volume by improving neurological function following middle cerebral artery occlusion in rats (Corona & Duchen, 2016; Culman, Zhao, Gohlke & Herdegen, 2007). Also, PPARγ activation by rosiglitazone imparts antidepressant‐ and anxiolytic‐like effects (Guo et al., 2017). …”

Rosiglitazone polarizes microglia and protects against pilocarpine‐induced status epilepticus

“…33,34 It has also been found that the PPAR γ agonist rosiglitazone imparts antidepressant-and anxiolytic-like effects. 28 Sun et al 35 found that PPAR γ agonist prevents neuronal loss and attenuates development of spontaneous recurrent seizures (SRS) through BDNF/TrkB signaling following pilocarpine-induced status epilepticus, and another report supports the idea that PPARγ agonist might be a potential neuroprotective agent for epilepsy by inhibiting oxidative stress and preventing astrocyte activation. 36,37 However, the role of the PPAR γ agonist rosiglitazone in protection against epilepsy from the point of microglia remains unknown.…”

“…Peroxisome proliferator‐activated receptor γ (PPAR γ) is a major modulator of lipid and glucose metabolism, inflammation, and organelle differentiation and has been suggested to play important roles in many neurological disorders . PPAR γ is a ligand‐activated transcription factor that belongs to the nuclear receptor family.…”

“…26 Studies have also shown that the noninflammatory reactive-like phenotype of microglia is adequate to drive epileptogenesis upon mTOR activation, which triggers the marked proliferation of astrocytes. 27 Peroxisome proliferator-activated receptor γ (PPAR γ) is a major modulator of lipid and glucose metabolism, inflammation, and organelle differentiation 28,29 and has been suggested to play important roles in many neurological disorders. 30,31 PPAR γ is a ligand-activated transcription factor that belongs to the nuclear receptor family.…”