TABLE 1.

Findings highlighting role of hypothalamic ER stress-related proteins in mediating appetite and weight gain and their modifications by antipsychotic drugs.

References	Study design	ER stress-related markers	Physiological role	Alteration in schizophrenia	Alteration during antipsychotic treatment
Won et al., 2009	1. Mice were injected with leptin after pretreatment with tunicamycin in the third ventricle. 2. Mice fed a HFD were co-treated with 4-PBA. 3. WB and PCR were used to detect the expression of STAT3 related with leptin and insulin signaling and ER stress markers in the hypothalamus.	PERK ↑ eIF2α↑ IRE1 ↑ XBP-1 ↑ CHOP ↑ GRP78 ↑	ER stress induced central leptin and insulin resistance and increased food intake and weight gain.	NR	NR
Cakir et al., 2013	1. Rats fed a HFD were co-treated with TUDCA after central injection of leptin. 2. N43/5 cells were treated with tunicamycin or thapsigargin after pretreated with 4-PBA or salubrinal. 3. RT-qPCR, RIA, and WB were used to detect the expression of POMC-processing-related proteins and ER stress markers in the ARC and PVN of rats, and in N43/5 cells.	p-PERK ↑ p-eIF2α↑	ER stress obstructed the post-translational processing of POMC, and induced leptin resistance, therefore regulating feeding.	NR	NR
Ozcan et al., 2009	1. Mice with specific knockout of XBP1 in neurons fed with HFD and ob/ob mice pretreated with 4-PBA and leptin were used to examine the effect of XBP1 in leptin signaling. 2. GTT and ITT were used to detect glucose metabolism and insulin function. WB was used to analyze ER stress markers and LepRB and STAT3 in hypothalamus.	PERK ↑ IRE-1α↑ XBP1 ↑ CHOP ↑	Hypothalamic ER stress induced leptin resistance and impaired glucose homeostasis, resulting in weight gain.	NR	NR
Contreras et al., 2014	1. Rats were centrally injected with ceramide to induce ER stress. 2. Then, an adenovirus encoding GRP78 wild-type was injected into the VMH of these rats and obese Zucker rats with higher ceramide C16 and C18. 3. RT-PCR, WB and IHC were used to detect expression of ER stress markers in the MBH and VMH, UCP1 and FABP3 in BAT, and leptin and insulin signaling in the VMH.	GRP78 ↑ p-IRE1 ↑ p-PERK ↑ p-eIF2α↑ ATF6α↑ CHOP ↑	1. Hypothalamic ER stress decreased BAT thermogenesis. 2. GRP78 overexpression in the VMH improved leptin and insulin resistance, increased BAT thermogenesis, causing weight loss.	NR	NR
Contreras et al., 2017	1. Rats were fed a HFD to induce hypothalamic ER stress, then the rats were treated with TUDCA. 2. GRP78 adenovirus was injected into the VMH of rats. 3. GTT and ITT were used to detect insulin function and glucose metabolism. RT-PCR, WB, and IHC were used to detect expression of ER stress markers, BAT thermogenesis markers, and key proteins of leptin signaling in the VMH.	GRP78 ↑ p-IRE1 ↑ p-PERK ↑ p-eIF2α↑ ATF6α↑ CHOP ↑	1. Hypothalamic ER stress inhibited BAT thermogenesis and WAT browning, and induced leptin and insulin resistance. 2. GRP78 overexpression in the VMH improved leptin and insulin resistance, and increased BAT thermogenesis and WAT browning, causing weight loss.	NR	NR
Henry et al., 2015	1. AgRP and POMC neurons were dissociated from transgenic mice with food deprived. 2. RNA-seq was used to detect the expression of ER stress markers in AgRP and POMC neurons.	BiP ↑ IRE1 ↑ XBP1 ↑ ATF6 ↑	XBP1 in AgRP and POMC neurons regulated food intake.	NR	NR
Park et al., 2020	1. Ob/ob mice from P4 to P16 postnatal were treated with TUDCA and leptin. 2. Ob/ob mice exposed to insulin and glucose were treated with TUDCA. 3. Ob/ob-POMC-Cre-ATG7loxP/loxP mice stimulated by glucose were treated with TUDCA. 4. GTT and ITT were used to detect insulin function and glucose metabolism. Using WB, RT-qPCR, IHC and M-FISH to examine ER stress markers and POMC projections in the hypothalamus.	ATF4 ↑ ATF6 ↑ GRP78 ↑ XBP1 ↑ CHOP ↑	ER stress inhibited leptin and insulin sensitivity, impaired glucose homeostasis and worsened POMC neuronal projections in the PVN, resulting in increased food intake and weight gain.	NR	NR
Deng et al., 2017	1. AgRP-ATF4 KO mice fed with HFD or injected with leptin were used to examine metabolic-related alteration. 2. AgRP-ATF4 KO mice were under cold exposure to detect thermogenic response. 3. GTT and ITT were used to detect insulin function and glucose metabolism. Using a rectal probe attached to a digital thermometer to measure rectal temperature in mice.	NR	AgRP ATF4 reduced insulin sensitivity, and decreased BAT thermogenesis and WAT browning.	NR	NR
Zhang et al., 2008	1. Normal chow-fed mice were injected with tunicamycin to induce ER stress. 2. Mice fed a HFD were injected with TUDCA. 3. IKKβCA was delivered bilaterally into the MBH of HFD mice, followed by insulin injection. 4. AgRP/IKKβlox/lox mice were fed with HFD. 5. Immunostaining and WB were used to examine the effects of IKKβCA on leptin and insulin signaling in the MBH. IP and WB were used to examine ER stress markers in the hypothalamus, and GTT was used to detect glucose metabolism.	p-PERK ↑ p-eIF2α↑	Hypothalamic ER stress activated IKKβ/NF-κB signaling, causing inflammation, glucose intolerance and central insulin and leptin resistance.	NR	NR
Wang et al., 2021	1. Rat primary astrocytes were pretreated with high glucose for 48 h, and then these cells were incubated with metformin for 1 h. 2. Rat primary astrocytes were treated with high glucose for 48 h after pretreatment with the AMPK activator AICAR for 1 h. 3. ELISA, co-IP, and WB were used to detect the ER stress markers and inflammatory cytokines in astrocytes.	p-PERK ↑ p-IRE1α↑ ATF6 ↑	Astrocytic ER stress induced inflammation by mediating AMPK.	NR	NR
He et al., 2021	1. Cultured astrocytes were treated with OLZ to detect the effects of OLZ on ER stress in astrocytes. 2. Rats were co-treated with OLZ and 4-PBA. 3. WB or IF were used to detect the expression of ER stress markers in astrocytes, and the GFAP, S100B, and TLR4 signaling in the hypothalamus.	p-PERK ↑ ATF6 ↑ IRE1 ↑ GRP78/BiP↑	1. ER stress induced astrocytes and TLR4 signaling activation. 2. Hypothalamic ER stress mediated food intake and body weight.	NR	1. OLZ induced astrocytic ER stress. 2. 4-PBA inhibited weight gain and astrocyte activation in the hypothalamus.
He et al., 2019	1. Rats were treated with OLZ for 1- and 8-day to detect the ER stress change in the hypothalamus. 2. OLZ and 4-PBA co-treated rats for 8 days. 3. WB was used to detect the expression of hypothalamic ER stress markers.	p-PERK↑ peIF2α↑ ATF4 ↑ GRP78/BiP ↑	Hypothalamic PERK-elF2α pathway mediated food intake and weight gain.	NR	OLZ activated hypothalamic PERK-eIF2α and IKKβ-NF-κB signaling.
Grajales et al., 2022	1. INS-1 cells were treated with OLZ or co-treated with OLZ and 250 μM TUDCA. 2. WB was used to detect the effect of OLZ in ER stress markers and ELISA was used to detect the concentration of insulin in INS-1 cells.	p-PERK ↑ p-eIF2α↑ IRE-1 ↑ XBP-1 ↑	ER stress inhibited insulin secretion.	NR	OLZ activated ER stress and inhibited insulin secretion, which were inhibited by TUDCA.
Lauressergues et al., 2012	1. Antipsychotics including DXMS, HAL, CLO, OLZ, RIS and QUE treated human hepatocyte cells for 24 h. 2. Rats were injected with CLO and OLZ for 1- and 3-h. 3. Hepatic lipid-related gene expression in cells and liver of rats was quantified by RT-qPCR and WB.	ATF4 ↑ CHOP ↑	ER stress activated the SREBP-1 and SREBP-2 pathways related to hepatic lipid accumulation.	NR	CLO, OLZ, and HAL activated the PERK pathway.

AgRP, agouti-related peptide; AgRP-ATF4 KO, agouti-related peptide neuron–specific ATF4 knockout; AgRP/IKKβ^lox/lox, AgRP neuron-specific knockout of IKKβ; ARC, arcuate nucleus; AICAR, 5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside; AMPK, adenosine 5′-monophosphate (AMP)-activated protein kinase; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; ATG7, autophagy related gene 7; BAT, brown adipose tissue; BiP, binding immunoglobulin protein; CHOP, C/EBP homologous protein; CLO, clozapine; co-IP, co-immunoprecipitation; DXMS, dexamethasone; ELISA, enzyme-linked immunosorbent assay; ER stress, endoplasmic reticulum stress; FABP3, fatty acid binding protein 3; GFAP, glial fibrillary acidic protein; GTT, glucose tolerance test; HFD, high-fat diet; IF, immunofluorescence; IHC, immunohistochemistry; IKKβ, inhibitor of nuclear factor kappa-B kinase subunit beta; IKKβ^CA, constitutively active IKKβ; IP, immunoprecipitation; IRE-1, inositol requiring enzyme 1; ITT, insulin tolerance test; LepRB, leptin receptor; LPS, lipopolysaccharide; MBH, mediobasal hypothalamus; M-FISH, multiplex fluorescence in situ hybridization; NF-κB, nuclear factor κB; Ob/ob-POMC-Cre-ATG7^loxP/loxP, leptin and POMC-specific ATG7 knockout; OLZ, olanzapine; PAKO, POMC neuron–specific ATF4 knockout; 4-PBA, 4-phenylbutyric acid; PCR, polymerase chain reaction; PERK, protein kinase R-like ER kinase; p-eIF2α, phosphorylated-eukaryotic initiation factor-2α; POMC, proopiomelanocortin; PVN, paraventricular nucleus; RIA, radioimmunoassay; RIS, risperidone; RNA-seq, RNA-sequencing; RT-qPCR, real-time quantitative polymerase chain reaction; S100B, S100 calcium binding protein B; SREBP-1, sterol regulatory element binding protein-1; SREBP-2, sterol regulatory element binding protein-2; STAT3, signal transducer and activator of transcription 3; TLR4, Toll-like receptor 4; TUDCA, tauroursodeoxycholic acid; UCP1, uncoupling protein 1; VMH, ventromedial nucleus of the hypothalamus; WAT, white adipose tissue; WB, western blotting; XBP-1, X-box-binding protein 1; NR, not reported.