Adipose Clocks: Burning the Midnight Oil

Abstract

Circadian clocks optimize the timing of physiological processes in synchrony with daily recurring and therefore predictable changes in the environment. Until the late 1990s, circadian clocks were thought to exist only in the central nervous systems of animals; elegant studies in cultured fibroblasts and using genetically encoded reporters in Drosophila melanogaster and in mice showed that clocks are ubiquitous and cell autonomous. These findings inspired investigations of the advantages construed by enabling each organ to independently adjust its function to the time of day. Studies of rhythmic gene expression in several organs suggested that peripheral organ clocks might play an important role in optimizing metabolic physiology by synchronizing tissue-intrinsic metabolic processes to cycles of nutrient availability and energy requirements. The effects of clock disruption in liver, pancreas, muscle, and adipose tissues support that hypothesis. Adipose tissues coordinate energy storage and utilization and modulate behavior and the physiology of other organs by secreting hormones known as "adipokines." Due to behavior- and environment-driven diurnal variations in supply and demand for chemical and thermal energy, adipose tissues might represent an important peripheral location for coordinating circadian energy balance (intake, storage, and utilization) over the whole organism. Given the complexity of adipose cell types and depots, the sensitivity of adipose tissue biology to age and diet composition, and the plethora of known and yet-to-be-discovered adipokines and lipokines, we have just begun to scratch the surface of understanding the role of circadian clocks in adipose tissues.

Keywords: PPARγ; Reverbα; adipocyte; adipose; circadian; clock.

Figure 1

Major sites of adipocyte accumulation in humans and rodents. Adipocytes accumulate in characteristic fatty deposits in humans, mice, and rats. White adipose tissues are subdivided into subcutaneous (shown in orange) and visceral (shown in yellow) adipose tissues. Visceral fat accumulation is associated with undesirable metabolic consequences while unhealthy lipodystrophy tends to cause preferential loss of subcutaneous fat. Brown adipose tissues (shown in brown) produce heat by burning fat stores and tend to be metabolically beneficial.

Figure 2

The circadian clock regulates lipid metabolism in white adipose tissue. Adipocytes are cells that specialize in storing triacylglycerols (TAGs). TAGs are hydrolyzed in a process called lipolysis to produce soluble energy in the form of glycerol and fatty acids (FAs) when other tissues demand energy. Lipolysis is stimulated by catecholamines, which are mainly produced in the adrenal medulla. TAGs from the circulation constitute the majority of the stored lipids in adipocytes. TAGs are produced by esterification of FAs that are imported from the circulation, derived from circulating lipids that are hydrolyzed by lipoprotein lipase (LPL), or are produced from other substrates, such as glucose, in a process called de novo lipogenesis. Insulin acts on adipocyte metabolism in several ways, as indicated in the figure. In addition, adipose tissue is an endocrine organ, secreting essential endocrine factors called adipokines. The circadian clock coordinates lipid energy metabolism, partly through regulating the expression of enzymes, transporters, and adipokines. Genes and adipokines marked in italics are reported to display diurnal oscillation in expression. Those that are shown in orange font are direct targets of BMAL1/CLOCK and/or found altered in mice with a disrupted intrinsic clock. Lpl, lipoprotein lipase; Dgat1/2, diglyceride acyltransferase 1/2; Mgat1, monoglyceride acyltransferase 1; Scd1, stearoyl-CoA desaturase-1; Elovl6, elongation of very long-chain fatty acids protein 6; Acsl1/4, acyl-CoA synthetase long-chain family member 1/4; Lpin1, phosphatidate phosphatase LPIN1; Ac1/2c, acetyl-CoA carboxylase 1/2; Fas, fatty acid synthase; Fabp4, fatty acid binding protein 4; Gpd1, glycerol-3-phosphate dehydrogenase 1; Agpat1/2, 1-acylglycerol-3-phosphate o-acyltransferase 4; Mogat2, monoacylglycerol acyltransferase 2; Gapdh, glyceraldehyde 3-phosphate dehydrogenase; Hk2, hexokinase 2; Pfkfb3, 6-phosphofructo-2-kinase/fructose-2,6-biphospatase 3; Pepck, phosphoenolpyruvate carboxykinase; Srebp1, sterol regulatory element-binding protein 1; Ppar α/γ, peroxisome proliferator-activated receptors α/γ; AdipoR1/2, adiponectin receptor 1/2; Pnpla2 (Atgl), patatin-like phospholipase domain containing/adipose triglyceride lipase; Lipe (Hsl), hormone-sensitive lipase; Ces1d (Tgh), carboxylesterase 1D/triacylglycerol hydrolase; FA, fatty acid; Wnt10a, wingless-type MMTB integration site family member 10a; Dvl2, disheveled segment polarity protein 2; Nr1d1 (RevErbα), nuclear receptor subfamily 1 group D member 1; slc2a4 (GLUT4), solute carrier family 2/glucose transporter type 4.