Tài liệu Báo cáo khoa học: Hypothalamic malonyl-CoA and CPT1c in the treatment of obesity pptx

MINIREVIEW

Hypothalamic malonyl-CoA and CPT1c in the treatment

of obesity

Michael J. Wolfgang and M. Daniel Lane

Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

Introduction

All living organisms must maintain a homeostatic

energy balance to survive fluctuations in environmental

conditions such as the scarcity of food. For higher

organisms, this involves storing energy as fat during

periods of an abundant food supply to hedge against

periods of food shortage. Today, humans have pushed

storage too far, to the point of widespread obesity.

Although obesity is preferable to starvation, this state

frequently leads directly or indirectly to serious pathol￾ogies including diabetes and heart disease. Interven￾tions to diminish adiposity beyond diet and exercise

would be greatly advantageous.

The central and peripheral nervous systems play cru￾cial roles in the regulation of metabolism, both glob￾ally and in various organ systems. Even in organisms

lacking a brain, such as Caenorhabditis elegans, the

nervous system plays a key role in maintaining energy

balance [1–4]. In more advanced, mammalian systems

there is compelling evidence for the control of energy

metabolism via the central nervous system (CNS),

notably through the regulation of feeding behavior

and satiety [5,6]. Furthermore, efferent neural signals

to peripheral sites have been shown to directly and ⁄ or

indirectly control diverse processes including beta-cell

Keywords

acetyl-CoA carboxylase; AMPK; carnitine

palmitoyl-transferase-1c; diabetes; fatty acid;

fatty acid synthase; malonyl-CoA;

neurometabolism; nutrient sensing; obesity

Correspondence

M. J. Wolfgang, Department of Biological

Chemistry, Johns Hopkins University School

of Medicine, Center for Metabolism and

Obesity Research, 475 Rangos Building,

725 N. Wolfe St., Baltimore, MD 21205,

USA

Fax: +1 410 614 8033

Tel: +1 443 287 7680

E-mail: [email protected]

(Received 10 August 2010, revised 29 Octo￾ber 2010, accepted 3 December 2010)

doi:10.1111/j.1742-4658.2010.07978.x

Metabolic integration of nutrient sensing in the central nervous system has

been shown to be an important regulator of adiposity by affecting food

intake and peripheral energy expenditure. Modulation of de novo fatty acid

synthetic flux by cytokines and nutrient availability plays an important role

in this process. Inhibition of hypothalamic fatty acid synthase by pharma￾cologic or genetic means leads to an increased malonyl-CoA level and sup￾pression of food intake and adiposity. Conversely, the ectopic expression

of malonyl-CoA decarboxylase in the hypothalamus is sufficient to pro￾mote feeding and adiposity. Based on these and other findings, metabolic

intermediates in fatty acid biogenesis, including malonyl-CoA and long￾chain acyl-CoAs, have been implicated as signaling mediators in the central

control of body weight. Malonyl-CoA has been hypothesized to mediate its

effects in part through an allosteric interaction with an atypical and brain￾specific carnitine palmitoyltransferase-1 (CPT1c). CPT1c is expressed in

neurons and binds malonyl-CoA, however, it does not perform the same

biochemical function as the prototypical CPT1 enzymes. Mouse knockout

models of CPT1c exhibit suppressed food intake and smaller body weight,

but are highly susceptible to weight gain when fed a high-fat diet. Thus,

the brain can directly sense and respond to changes in nutrient availability

and composition to affect body weight and adiposity.

Abbreviations

ACC, acetyl-CoA carboxylase; AMPK, 5¢ AMP-activated protein kinase; CNS, central nervous system; CPT, carnitine palmitoyltransferase;

FAS, fatty acid synthase.

552 FEBS Journal 278 (2011) 552–558 ª 2010 The Authors Journal compilation ª 2010 FEBS