Diabetes Research and Clinical Practice - Volume 120 - Supplement 1

WAT upon cold exposure. Increasing the amount or activity

of brown/beige fat has been considered as an appealing

approach for the treatment or prevention of obesity and

related metabolic disorders. The energetic processes executed

by BAT require a readily available fuel supply, which includes

glucose and fatty acids (FAs). FAs become available by cellular

uptake, de novo lipogenesis, and from release of fat stored in

multilocular lipid droplets in brown adipocytes. BAT also

possesses a great capacity for glucose uptake and metabo-

lism, as well as an ability to regulate insulin sensitivity. I will

discuss our recent findings on cold-induced lipid dynamics in

brown and white adipose tissue of mice using highly sensitive

liquid chromatography coupled with mass spectrometry

lipidomics analyses.

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HOXC10 suppresses browning of white adipose tissues

Weiping HAN

Joslin Diabetes Center and Harvard University,

Boston, MA, USA

As increased thermogenesis in white adipose tissue (WAT), or

browning, promotes energy expenditure, significant efforts

have been invested to determine the molecular players invol-

ved in this process. Here, we show that HOXC10, a homeobox

domain-containing transcription factor expressed in sub-

cutaneous (SubQ) WAT, is a suppressor for genes involved in

the process of browning. Ectopic expression of HOXC10 in

adipocytes suppresses brown fat genes. Conversely, depletion

of HOXC10 in adipocytes and myoblasts increases expression

of brown fat genes. HOXC10 protein level inversely correlates

with brown fat genes in SubQ WAT of cold exposed mice.

Expression of HOXC10 in mice suppresses cold-induced

browning in SubQ WAT and abolishes the beneficial effect of

cold exposure on glucose clearance. HOXC10 exerts its effect,

at least in part, by suppressing PRDM16 expression. Taken

together, we propose that HOXC10 is a key negative regulator of

the process of browning in WAT.

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Inactivation of the E-Prostanoid 3 receptor gene causes

adiposity and insulin resistance via altering white adipose

tissue metabolism

Hu XU

, Xiaoyan ZHANG

, Youfei GUAN

Advanced Institute for

Medical Sciences, Dalian Medical University, Dalian, China

Prostaglandins E2 (PGE2) is the predominant prostaglandin

produced in white adipose tissue (WAT) and plays an

important role in adipogensis and adiposity. Among four

PGE2 receptors, the EP3 receptor is most abundantly expressed

in WAT. In mice, the EP3 gene gives rise to three isoforms,

namely EP3

, EP3

and EP3

, which differ only at their

C-terminal tails and are produced by alternative splicing. To

date, the role of the EP3 and each of its isoforms in the

regulation of WAT remains incompletely characterized. In

the present study, we found that the expression of all EP3

isoforms were significantly down-regulated in WAT of several

obese murine models including db/db mice and high-fat

diet-induced obese mice. Genetic ablation of total EP3 receptor

gene (EP3-/- mice) or selective deletion of the EP3

and

EP3

isoforms (EP3

mice) led to an obese phenotype, with

increased food intake, decreased motor activity, reduced

insulin sensitivity and imbalanced lipid metabolism fea-

tured as enhanced adipogenesis. Terminal differentiation of

preadipocytes and mouse embryonic fibroblasts (MEFs) was

markedly facilitated by either pharmacological blockade of

the EP3 receptor or genetic targeting of the EP3

and EP3

isoforms. The inhibition of adipogenesis by the EP3 and the

EP3

and EP3

was mainly through the cAMP/PKA/CREB

pathway. In addition, the EP3-/- and EP3

mice also exhibited

increased lipolysis in WAT, which is mainly mediated by the

suppression of the cAMP/PKA/HSL pathway. Taken together,

the EP3 receptor is critical for the maintenance of normal WAT

function, where inactivation of the EP3 promotes adiposity via

facilitating adipogenesis and increases insulin resistance via

enhancing lipolysis.

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Regulation of hepatosteatosis and obesity by sphingolipids

Tae-Sik PARK

Department of Life Science, Gachon University,

Sungnam, Gyeonggido, Korea

Sphingolipids are implicated in etiology of chronic metabolic

diseases including cardiovascular diseases and diabetes.

In this study, we investigated whether

de novo

sphingo-

lipid biosynthesis is associated with development of adipose

tissues. SPTLC2, a subunit of serine palmitoyltransferase, was

transcriptionally upregulated in adipose tissues of obese mice

and during differentiation of 3T3-L1 cells. SPTLC2 knockdown

suppressed expression of adipogenic genes and lipid accu-

mulation in 3T3-L1 cells. To confirm this, we have developed

adipocyte-specific SPTLC2 deficient (aSPTLC2 KO) mice that

have lipodystrophic phenotype even with high fat diet feeding.

The cell size and mass of adipocyte tissue were reduced

dramatically and expression of adipogenic genes was down-

regulated. Whereas, the fatty acids destined to the adipose

tissue were accumulated by increased uptake into liver and

caused hepatic steatosis. aSPTLC2 KO mice fed a high fat diet

did not increase the body weight but fasting glucose levels

were elevated and developed systemic insulin resistance.

Although adenoviral SPHK2 overexpression in liver did not

recover lipodystrophic phenotype, the floxed mice showed

increased fat mass. This is in part due to downregulation of S1P

receptor 1 in adipose tissue of aSPTLC2 KO mice and SPTLC2-

suppressed 3T3-L1 cells. Collectively, our observations sug-

gest that tight regulation of

de novo

sphingolipid biosynthesis

and S1P signaling plays an important role in adipogenesis and

hepatosteatosis.

S20-5

Targeting fat metabolismand energy expenditure inmetabolic

disease

Kyle HOEHN

Garvan Institute of Medical Research, Sydney,

Australia

Excess fat accumulation in peripheral tissues is a risk factor

for insulin resistance and type 2 diabetes. Calorie restriction

and exercise are the safest and most effective ways to decrease

excess lipid storage; however, poor patient compliance

and disability limit the effectiveness of these approaches.

Therefore, there is an unmet medical need to develop

drugs that promote fat loss. My laboratory has investigated

three approaches to reduce fat mass including increasing

fat oxidation, reducing lipogenesis, and increasing energy

expenditure. We have found that increasing fat oxidation or

reducing lipogenesis by targeting acetyl-CoA carboxylase

enzymes is not sufficient to promote fat loss because tissues

compensate by altering carbohydrate metabolism and fat

uptake. However, increasing energy expenditure by mitochon-

drial uncoupling represents a viable approach if safety can be

improved through the development of mitochondria-specific

small molecule mitochondrial uncouplers.

Hot Topics in Diabetes and Obesity (I)

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Molecular mapping of insulin action and insulin resistance

David E. JAMES

Charles Perkins Centre, School of Life and

Environmental Science, Sydney University, Sydney, Australia

Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1

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