Diabetes Research and Clinical Practice - Volume 120 - Supplement 1

Department of Psychiatry, National Cheng Kung University

Hospital, College of Medicine, National Cheng Kung University,

Department of Family Medicine, National Cheng Kung University

Hospital, College of Medicine, National Cheng Kung University,

Tainan, Taiwan

Background:

Several stress-induced psychiatric illnesses,

including social defeat are associated with an increased risk

of developing metabolic disturbances. The stress of social

defeat activates the sympathetic nervous system, and recruits

the hypothalamic-pituitary-adrenal axis (HPA) to change the

neurotransmitter release in several brain regions, and might

result in long-lasting physiological changes, including

metabolic disturbances such as obesity and metabolic syn-

drome. Although the relationship between metabolic distur-

bances and stress were well established, the mechanisms

linking social defeat and metabolic disorders remain obscure.

Hepassocin is an interneukin-6-regulated hepatokine, and

exerts an activity to induce insulin resistance through an ERK-

dependent pathway. In addition, the expressions of hepasso-

cin were increased in social defeat animal model. Thus, the

aim of this study is to investigate the role of hepassocin in

stress-induced insulin resistance.

Material and methods:

The chronic social defeat model was

established with C57BL/6J and CD-1 mice. C57BL/6J mice that

are repeatedly subjected to bouts of social defeat by a

larger and aggressive CD-1 mouse for 10-day results in the

development of a depressive-like syndrome. Insulin sensitiv-

ity and glucose utility in animals were assessed by insulin

and glucose tolerance tests, as well as HOMA-IR. The

concentrations of interleukin-6, cortisol, and hepassocin

weremeasured by commercialized ELISA kits. The expressions

of hepassocin and interleukin-6 receptor were determined by

western blots.

Results:

In the present study, we found that chronic social

defeat not only induced glucose intolerance, but also aggra-

vated high fat diet induced insulin resistance in C57BL/6J mice.

In addition, chronic social defeat in mice increased the plasma

concentrations of hepassocin, cortisol, and interleukin-6.

Treatment of cortisol increased the translocation of interleu-

kin-6 receptor to cell membrane, and interleukin-6 increased

the expression of hepassocin in hepatocytes. Furthermore, co-

treatment of cortisol, and interleukin-6 synergically facilitated

the expression of hepassocin, and thus contributed to the

development of insulin resistance.

Conclusion:

Chronic social defeat increased the concentra-

tions of both cortisol and interlekin-6 in circulation to

synergically increase the expression of hepassocin. The

elevated hepassocin levels in circulation further contribute

to systemic insulin resistance.

OL02-2

The role of casein kinase 2 in ER stress associated pancreatic

cell failure

Yuki MATSUURA

, Tomoko TAKAI

, Tomokazu MATSUDA

Emi TERASHI

, Ayumi KANNO

, Syun-ichiro ASAHARA

Yoshiaki KIDO

1,2

Kobe University Graduate School of Health

Sciences,

2Division of Diabetes and Endocrinology, Department of

Internal Medicine, Kobe University Graduate School of Medicine,

Japan

Objective:

During the development of type 2 diabetes, endo-

plasmic reticulum (ER) stress not only leads to insulin

resistance but also causes pancreatic

cell failure. We have

revealed that ER stress affected the pancreatic

cell mass.

Recently, casein kinase 2 (CK2) inhibitors have attracted

attention as anticancer drugs. CK2 inhibitors suppress prolif-

eration and induce apoptosis in cancer cells, but do not affect

non-cancer cells. The difference of ER function between cancer

cells and normal cells has been attributed to one of these

mechanisms. Furthermore, inhibition of CK2 is reported to

have protective function in diabetic nephropathy, and

promote beige adipocyte biogenesis. This implies that CK2

inhibitors might be a promising approach to prevent or treat

diabetes and impaired glucose tolerance. However, the effect

of CK2 on pancreatic

cells remains to be elucidated.

Therefore, we analyzed the role of CK2 in ER stress-associated

pancreatic

cell failure.

Methods:

The function of CK2 in MIN6 cells and isolated islets

of mice were evaluated by molecular biological approach. CK2

inhibitor, emodin, was administered to pancreatic

cell-

specific C/EBP

transgenic (TG) mice, which is our original

diabetic model mice that exhibit reduction of pancreatic

cell

mass associated with ER dysfunction and present with mild

hyperglycemia without insulin resistance (JCI, 2010).

Results:

Under normal conditions, CK2

was mainly localized

in the nucleus and CK2

was mainly localized in the cytoplasm

in MIN6 cells. However, under conditions of ER stress, CK2

translocated to the nucleus and colocalized with C/EBP

Furthermore, in C/EBP

-overexpressing MIN6 cells and the

isolated islets of TG mice, both CK2

and CK2

were also

colocalized with C/EBP

in the nucleus. Moreover, pull-down

assay with GST-C/EBP

and recombinant CK2 revealed that C/

EBP

directly combined with CK2 in vitro. Unfolded protein

response, indicated by expression of C/EBP

, CHOP, and

phospho-c-Jun, was suppressed by deletion of CK2

in MIN6

cells. The CK2 inhibitor, emodin, had no effect on blood

glucose levels and body weight in TG mice ad libitum.

However, intraperitoneal glucose tolerance test revealed that

emodin treatment remedied glucose intolerance in TG mice.

Conclusion:

We confirmed that CK2 interacts with C/EBP

under ER stress, and suggest that CK2 inhibitors might reduce

insulin resistance and play a protective role in pancreatic

cells.

OL02-3

A surge of appetite regulating hormone, ghrelin, and its

relevance to motivation for the initiation of voluntary exercise

in mice

Yuji TAJIRI

*, Kento HARA

, Yusuke SAKAI

Hiroharu MIFUNE

, Ryouichi MITSUZONO

Masayasu KOJIMA

, Kentaro YAMADA

Division of

Endocrinology and Metabolism, Kurume University School of

Medicine,

Institute of Animal Experimentation, Kurume University

School of Medicine,

Department of Exercise Physiology, Institute of

Health and Sports Science, Kurume University,

Molecular Genetics,

Life Science Institute, Kurume University, Japan

We previously reported that voluntary exercise contributed to

an amelioration of abnormal feeding behavior with a con-

comitant restoration of ghrelin production in obese rats,

suggesting a putative relationship between exercise and

ghrelin. Because ghrelin is related to higher motivation and

hyperactivity as an exploring behavior for food, we investi-

gated the relevance of ghrelin as an initiator of voluntary

exercise as well as feeding behavior.

The animals were housed under a 12 h light dark cycle (light on

7:00

–

19:00). Four-week-old male wild type (WT) mice were

either fed control chow diet (WT-CD) or high fat diet (60 kcal%

fat: WT-HFD) for 12 weeks. Ghrelin knockout mice at the same

age were fed CD for the same period (GKO-CD). At 16weeks old,

they were moved individually into acrylic metabolic chambers

equipped with running wheel for the measurement of food

intake (FI) and wheel running count (COUNT) as voluntary

exercise performance on a minute by minute basis. After all

measurements, they were sacrificed under isoflurane anes-

thesia and blood samples were collected at 8 time points

during the day for the measurement of plasma active ghrelin

concentrations by RIA.

WT-HFD revealed an obvious weight gain and abnormal

feeding behavior as an increase of FI during light phase

compared to WT-CD. Plasma ghrelin levels in WT-CD showed

a bimodal diurnal rhythm with its peaks at 7:00 and 19:00. In

Oral Presentations / Diabetes Research and Clinical Practice 120S1 (2016) S40

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