β-Adrenoceptor Signaling Networks in Adipocytes for Recruiting Stored Fat and Energy Expenditure

Abstract

THE ADIPOCYTE IS LIKE A BANK: a place to store excess (caloric) cash in times of plenty, and from which one can withdraw savings during "lean times." The β-adrenoceptors (βAR) are the gateways to this mobilization of fat to be consumed in other tissues. This review discusses the βAR signaling pathway(s) in white and brown adipocytes. Studies in rodent models show that brown adipocytes nestled with white fat depots correlate with and are considered a key enabling factor in resistance to diet-induced obesity. Since it is now recognized that adult humans have brown adipocytes, knowing the steps in these signaling pathways may provide the opportunity to manipulate adipocytes to be net consumers of energy.

Keywords: adipocyte; adrenergic; brown; kinase; signaling; white.

Figure 1

Scheme for βAR signaling cascades controlling lipolysis in adipocytes. βARs activate adenylyl cyclase through their coupling to the heterotrimeric Gs, producing cAMP (green dots) from ATP (yellow dots) to activate the cAMP-dependent protein kinase (PKA), allowing the catalytic subunits (PKA-C2) to be released from the holoenzyme that is anchored to the plasma membrane (AKAP). PKA phosphorylates (blue dots) lipases (HSL: hormone sensitive lipase) and lipid droplet binding proteins such as perilipins (Peri A; Peri B). Adipose triglyceride lipase (ATGL) is phosphorylated but not by PKA. The fatty acids released from triglyceride are chaperoned out of the cell by lipid binding proteins (aP2) and exported through fatty acid transport proteins (FATP).

Figure 2

βARs activate ERK MAPK in addition to PKA: the β₂AR mechanism as an example. Upon catecholamine activation, PKA is activated (step 1), and phosphorylates the receptor at intracellular sites (red circles; step 2a). The receptor is also phosphorylated by G protein-coupled receptor kinase (GRK) at multiple sites in the C-terminus (step 2b). PKA phosphorylation interdicts interaction with Gs to favor Gi, while GRK recruits β-arrestin, promoting ERK activation (step 3). β₂AR is subject to rapid desensitization and internalization (step 4), whereupon phosphatases remove the phosphates and the receptor is recycled back to the plasma membrane.

Figure 3

A unique dual signaling mechanism by β₃AR. (A) The receptor can couple to both Gs and Gi to activate PKA (step 1a) and ERK (step 1b). The shaded gray arrows point to subsequent downstream cellular effects. (B) Preadipocytes were transfected or not (NT) with hemagglutinin (HA)-tagged β₃AR and differentiated. (a) Expression of aP2 and β₃AR mRNA as a function of differentiation on the indicated days. Levels of aP2 are maximal by day 4. Cyclophilin RNA (Cyclo) is the internal control. (b) Phospho-ERK1/2 in cell lysates in response to the β₃AR agonist CL316243 (CL) in the absence or presence of pertussis toxin (PTX; n = 3; mean ± SD). (c) Level of c-Src co-precipitated with β₃AR (n = 3; mean ± SD). (Adapted from Cao et al., 2000).

Figure 4

β-agonists increase activation of p38 MAPK in cultured human subcutaneous adipocytes. (A) Western blot measuring isoproterenol (Iso) concentration-response for phospho-p38 MAPK (P-p38). (B) Western blot comparing P-p38 response to 15 min treatment with Iso, EGF and the positive control cell stressor Anisomycin. All samples shown are independent biological replicates.

Figure 5

βAR activation of thermogenesis through p38 MAPK. Direct targets of p38 MAPK include peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and ATF-2. These target the genes for Pgc-1α and Ucp1. The tandem arrows between PKA and the MAPK module are not yet biochemically defined.

Figure 6

Signaling networks of the βARs in adipocytes. Each of the three βARs is able to activate similar pathways: PKA, ERK, and p38 MAPK. However the order and number of steps involved varies, such that β₃AR represents what we term “concurrent” coupling to Gs vs. Gi, vs. the β₂AR type of “processive” coupling. Less is known about the details of β₁AR. Because β₁AR also contains one of the PXXP motifs as in β₃AR, but it is also phosphorylated, we have provisionally termed in “mixed-mode” coupling. The shaded gray arrows point to subsequent downstream cellular effects.