Diabetes Research and Clinical Practice - Volume 120 - Supplement 1 - October 2016

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Activins, members of TGF β superfamily proteins, are known to
play a pivotal role in the reproductive and developmental
processes and their variety of functions have recently been
explored in many cells and tissues, while the role in glucose
metabolism is poorly understood. Here we show that admin-
istration of Activin B, which is mainly produced in liver in the
fasted state, significantly reduces blood glucose levels in both
obese diabetic mice and insulin deficient diabetic mice, while
this effect is completely canceled by co-administration of
FSTL-3, known as an inhibitory molecule for TGFβ superfamily
proteins. Activin B exerts glucose lowering effects through
suppression of gluconeogenesis, induction of FGF21 and
increased insulin secretion. Although expression of Activin B
is not altered by obesity, expression of FSTL-3 in adipocytes,
strongly correlates with BMI and insulin resistance inmice and
humans. Indeed, suppression of FSTL-3 markedly improves
glucose homeostasis in obese mice. Thus, Activin B produced
by the liver contributes to the maintenance of glucose levels
and insulin sensitivity under the lean condition and obesity
increases the production of FSTL3 thereby suppressing the
functions of Activin B leading to insulin resistance and
dysregulation of glucose homeostasis.
Hot Topics in Diabetes and
Obesity (II)
S35-1
Role of CRTC2 in the control of glucose metabolism
Hye-Sook HAN 1, Byeong Hun CHOI1, Jun Seok KIM1,
Geon KANG 1, Seung-Hoi KOO1. 1Division of Life Sciences, College of
Life Sciences & Biotechnology, Korea University, Seoul, Korea
Liver plays a major role in maintain glucose homeostasis in
mammals. Under the starvation, glucose production is
increased in the liver to provide enough fuels for critical
organs such as brain and red blood cells. Short-term fasting
mainly activates glycogenolysis in the liver, and a longer-
term fasting triggers the activation of gluconeogenesis that
utilizes various non-carbohydrate precursors such as
lactate, amino acids, and glycerol to meet the body’s need for
glucose. Interestingly, activation of gluconeogenesis is in large
part achieved by a transcriptional mechanism in response to
pancreatic hormone glucagon and adrenal glucocorticoid.
While glucocorticoid signals through a nuclear receptor
glucocorticoid receptor, glucagon elicits its effects by inducing
cAMP-dependent pathway in the liver, utilizing CREB and
CREB regulated transcription coactivator 2 (CRTC2) as proximal
transcriptional complex. Increased hepatic glucose production
under insulin resistance or type 2 diabetes is one of the major
causes for hyperglycemia, and it was shown that hyperactiva-
tion of CREB/CRTC2 signals could be in part responsible for
such phenomenon. In this talk, we would like to delineate the
mechanistic insight into the role of CRTC2 in the control of
hepatic glucose metabolism by using in vivo mouse models.
S35-3
Significance of adiponectin accumulation in vasculature
Norikazu MAEDA 1,2, Iichiro SHIMOMURA1. 1Department of
Metabolic Medicine, Graduate School of Medicine, Osaka University,
2 Department of Metabolism and Atherosclerosis, Graduate School of
Medicine, Osaka University, Osaka, Japan
Our group discovered adiponectin from human fat tissue in
1996 and established the measurement of circulating adipo-
nectin concentration by using ELISA in 1999. Adiponectin
is characterized as follows: (1) Plasma concentration range
from 1 to 30 μg/mL in human adults, which is 103- to 10 6-fold
higher than the levels of ordinary cytokines and hormones.
(2) Circulating adiponectin levels paradoxically decrease in
obesity, especially in visceral fat-accumulated obesity.
Clinical and experimental studies evidently showed that
adiponectin directly effects on cardiovascular tissues and
exhibits cardiovascular protective function, suggesting the
direct axis of fat and cardiovascular system. Importantly, we
recently demonstrated the existence of adiponectin protein in
the cardiovascular tissues and its localization was changed
when these tissues were injured. However, molecular mech-
anism for the adiponectin accumulation in cardiovascular
tissues has not been fully understood. Lodish’s group previ-
ously demonstrated that T-cadherin is a receptor for multi-
meric forms of adiponectin (Hug C et al. PNAS 2004).
T-cadherin is an atypical glycosylphosphatidylinositol (GPI)-
anchored cadherin cell surface glycoprotein. Interestingly,
T-cadherin knockout mice mimick the adiponectin knockout
cardiovascular phenotype (Denzel MS et al. JCI 2010). In this
symposium, I would like to talk about recent advances of
adiponectin research in view of the cardiovascular protective
action of adiponectin via T-cadherin.
S35-4
Hypothalamic inflammation in high fat diet-induced obesity
Min-Seon KIM1. 1Division of Endocrinology and Metabolism, Asan
Medical Center, University of Ulsan College of Medicine, Seoul, Korea
A prolonged consumption of high fat diet (HFD) leads to
hypothalamic inflammation in rodents. HFD-fed rats dis-
played increased expression of proinflammatory cytokines
[interleukin-1 (IL-1), IL-6 and tumor necrosis factor-α (TNFα)]
and activation of inflammatory signaling [c-Jun N-terminal
kinase (JNK) and the IκB kinase-β /nuclear factor-κB (IKKβ-
NFκB)] in their hypothalamus. Activation of hypothalamic
inflammatory signaling pathways is suggested as an import-
ant mechanism underpinning overnutrition-induced leptin
and insulin resistance. While it is evident that HFD induces
hypothalamic inflammation, a relative contribution and
interactions of neurons, glial cells, and immune cells in this
process are not largely unveiled. A recent study has reported a
rapid activation of hypothalamic microglia upon HFD feeding,
which is evidenced by morphological changes and increased
number. In my talk, I will present our recent data which
suggest a critical contribution of hypothalamic macrophages
in hypothalamic inflammation observed in HFD-induced
obesity.
Hot Topics in Diabetes and
Obesity (III)
S38-1
Feeding-induced activation of beta-catenin/TCF signal
transduction in hypothalamic neurons
Dave GRATTAN1. 1University of Otago, New Zealand
Polymorphisms in the TCF7L2 gene are associated with
increased risk of type-2 diabetes and obesity. TCF7L2 is a
transcriptional co-factor that binds with β-catenin to promote
gene transcription in the canonical Wnt/β -catenin pathway,
and studies have focused on this pathway in the pancreas
as a causal link to type-2 diabetes. The role of the brain in
glucose homeostasis is increasingly recognised, however,
and impaired neuronal Wnt signalling may contribute to
development of diabetes. Here, we investigated whether
the Wnt/β-catenin pathway is regulated in the hypothalamus
during the normal physiological responses to food intake.
We observed that feeding acutely induced stabilisation of
β-catenin in neurons in specific hypothalamic nuclei
involved in metabolic regulation, associated with increased
Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1–S39 S26