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-adrenergic stimulation, fasting, and dietary fat loading
Divisions of 1Medical Genetics and 2Gastroenterology, Research Centre, Hôpital Ste.-Justine, Montreal, Quebec H3T 1C5; 3Division de Kinésiologie, Département de Médecine Sociale et Préventive, Université Laval, and 4Centre de Recherche de l'Hôpital Laval and Centre de Recherche sur le Métabolisme Énergétique de l'Université Laval, Département d'Anatomie et de Physiologie, Faculté de Médecine, Université Laval, Quebec, Canada G1K 7P4
Submitted 23 April 2003 ; accepted in final form 2 March 2004
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ABSTRACT |
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-adrenergic stimulation, fasting, and dietary fat loading. Intraperitoneal administration of the 3-adrenergic agonist CL-316243 caused a greater increase in nonesterified fatty acid level in controls (0.33 ± 0.05 mmol/l) than in HSL–/– mice (0.12 ± 0.01 mmol/l, P < 0.01). Similarly, in isolated adipocytes, lipolytic response to CL-316243 was greatly reduced in HSL–/– mice compared with controls. Fasting for 
48 h produced normal mobilization and oxidation of fatty acids in HSL–/– mice, as judged by similar values of respiratory quotient and oxygen consumption as in HSL+/+ controls. In isolated adipocytes, lipolysis in the absence of -adrenergic stimulation was 1.9-fold greater in HSL–/– than in HSL+/+ cells (P < 0.05), increasing to 6.5-fold after fasting (P < 0.01). After 6 wk of a fat-rich diet containing 31.5% of energy as lipid, weight gain of HSL–/– mice was 4.4-fold less than in HSL+/+ mice (P < 0.01), and total abdominal fat mass was 5.2-fold lower in HSL–/– than in HSL+/+ mice (P < 0.01). In white adipose tissue, HSL is essential for normal acute -adrenergic-stimulated lipolysis and permits normal triglyceride storage capacity in response to dietary fat loading. However, HSL-independent lipolysis can markedly increase during fasting, both in isolated adipocytes and in intact mice, and can mediate a normal flux of fatty acids during fasting. lipid energy metabolism
-adrenergic agonists and glucagon and decreased by insulin (12). After -adrenergic stimulation, HSL is phosphorylated at several serine residues by cAMP-dependent protein kinase A (12) and by extracellular signal-regulated kinase (8). Phosphorylated HSL translocates from the cytoplasm to the surface of the lipid droplet (6). Conversely, a lipid droplet surface protein also phosphorylated by protein kinase A, perilipin A, shifts to the cytoplasm in response to lipolytic stimulation (2). HSL also reportedly binds to a docking protein, lipotransin (29), and to fatty acid-binding protein (27). HSL was previously considered to be an essential and possibly the only catalyst of adipose tissue lipolysis (12). This focused interest on HSL as a candidate molecule for obesity and stimulated different groups to create HSL-deficient mice by gene targeting (9, 22, 30). The expected manifestations of HSL deficiency were marked obesity, adipocyte hypertrophy, and a lack of lipolytic activity. In fact, the masses of subcutaneous and abdominal fat depots are significantly reduced in HSL-deficient mice compared with those of normal littermates. Histologically, white adipose tissue of HSL–/– mice contains a mixture of normal or small cells and hypertrophied adipocytes. Also, in isolated HSL–/– adipocytes, nonstimulated (basal) lipolytic activity is at least as great as that of normal adipocytes, proving the existence of non-HSL-mediated pathway(s) of adipocyte lipolysis.
HSL-deficient mice also have phenotypes in other cells that express HSL, including decreased glucose-stimulated insulin secretion in pancreatic -cells (25), adrenal cortex accumulation of cholesteryl esters in adrenal cortex (17), and failure of male germ cell development with male sterility (4).
Here, we explore the importance of HSL-independent pathways in white adipose tissue energy homeostasis under conditions of increased fatty acid flux: dietary fat loading, fasting, and acute systemic 3-adrenergic stimulation.
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MATERIALS AND METHODS |
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Activity measurements. We measured horizontal displacement of 4-mo-old male mice by means of the infrared DigiscanSystem (Accuscan). Mice were housed individually in cages. Infrared beam breaks, generated by displacement of the mouse, were recorded every minute for 24 h (20). Activity levels were analyzed for the entire period as well as for two 6-h periods: dark (7:00 PM to 1:00 AM) and light (7:00 AM to 1:00 PM). To attempt to control for the effect of body mass on energy expenditure for movement, we also analyzed the product of activity times body weight for each of the above periods.
Biochemical measurements. Blood samples were obtained by capillary sampling from the tail or by intracardiac puncture. For tissue samples, the organs were removed, weighed, and rapidly frozen after exsanguination and decapitation. Blood metabolite and hormone measurements were as described (30). 3-Hydroxybutyrate (3HB) was measured with a kit (310-A; Sigma, St. Louis, MO). We measured liver and carcass triglyceride (TG) content as described (28), after saponification of carcasses or of 200 mg of liver in a 2:1 solution of ethanol and 30% KOH (wt/vol) for 48 h at 60°C and then addition of 0.5–0.54 ml of 1 M MgC12, centrifugation at 16,000 g for 30 min, and removal of the supernatant. TG content was assayed with a kit (320-A, Sigma).
Acute -adrenergic stimulation in vivo.
Seven 3-mo-old male HSL+/+ and HSL–/– mice were injected intraperitoneally with 1 mg/kg of the selective 3-adrenergic receptor agonist CL-316243 (a gift from Wyeth-Ayerst Research, Princeton, NJ). As controls, seven HSL+/+ and HSL–/– mice were injected with saline. Blood samples were taken before and 15 min after injection. Preliminary studies in normal mice sampled at 0, 5, 15, and 30 min after CL-316243 injection had demonstrated a peak of plasma free fatty acids (FFA) at 15 min (not shown).
Fasting tests. Groups of HSL–/– and normal mice were fasted for 48 h starting at 9:00 AM and compared with ad libitum-fed controls of each genotype. After being tested, mice were anesthetized, weighed, and exsanguinated by cardiac puncture. Organs were quickly weighed and then frozen. We studied 3- and 8-mo-old female mice and 7-mo-old male mice.
Indirect calorimetry.
Mice were housed individually in a 1-liter Plexiglas metabolic chamber and allowed to adapt to the new environment for 48 h before oxygen consumption (
O2) and carbon dioxide production (CO2) were measured with an open-circuit system as described (23). Briefly, ambient air was drawn through the chamber at a flow rate of 750 ml/min. O2 and CO2 analyzers were from Applied Electrochemistry, models S3A1 and N22M. An automatic valve-driver interface allowed for the alternate sampling in eight metabolic chambers. Between the intermittent measurements, all chambers, except that from which air was sampled for gas analyses, were ventilated at an airflow rate equal to that passing through the sampling chamber.
Dual-energy X-ray absorptiometry evaluation of fat and lean body masses. Dual-energy X-ray absorptiometry (DEXA) was performed with a PIXImus instrument (Lunar, Madison, WI).
Lipolysis measurements in isolated adipocytes. Mice were either fasted from the previous morning or allowed access to food until the experiment. Adipocyte isolation was performed between 9:00 and 10:00 AM. The in vitro lipolysis assay was based on previous methods (19). Briefly, adipocytes were isolated from 250 mg of perigonadal fat of female mice by collagenase digestion (24) in Krebs-Ringer bicarbonate buffer (pH 7.5) containing 4% bovine serum albumin (KRBA; Roche Diagnostics, Laval, QC, Canada), 5 mM glucose, 1 mg/ml collagenase (GIBCO-BRL, Burlington, VT), and 0.1 mM ascorbic acid (Sigma) for 30 min in a shaking bath at 37°C under a gas phase of 95% O2-5% CO2. Adipocytes were filtered through a nylon mesh and washed three times with KRBA. Cell concentrations were determined by microscopy (3) and adjusted to 3,000 cells/50 µl, a concentration that we found to give optimal reproducibility. Lipolytic agents (10–5 M isoproterenol, 10–5 M CL-316243, 10–5 M norepinephrine, 10–5 M forskolin, and 10–3 M dibutyryl-cAMP) were from Sigma, except for CL-316243 (Wyeth-Ayerst Research, Princeton, NJ).
Lipolysis was assayed in 10 µM N6-(L-2-phenylisopropyl)adenosine and 5 µg/ml adenosine deaminase (Sigma) plus lipolytic agents or KRBA for basal lipolysis and blanks. Incubations were for 2 h at 37°C under 95% O2-5% CO2. Reactions were stopped by heating at 80°C for 2 min and then freezing at –20°C. Basal lipolysis was defined as glycerol release in the absence of lipolytic stimulation. Triplicate measurements were performed for each mouse. At least three mice of each genotype were tested. Glycerol was measured in a Wallac 1420 luminometer (Perkin-Elmer, Woodbridge, ON) using bacterial NADH-linked luciferase to measure glycerol release from adipocytes (14). Light production was quantified using a standard curve ranging from 0.02 to 0.12 nmol of glycerol. Lipolysis was expressed as nanomoles of glycerol per 106 cells per hour.
High-fat diet, food intake, and food efficiency. We studied 4-mo-old males: seven HSL+/+, seven HSL+/–, and six HSL–/–. Mice were habituated for 1 wk to a liquid diet containing 4.03% fat, 16.40% protein, and 68.94% carbohydrate by weight (Bio-Serve, Frenchtown, NJ) and then switched for 6 wk to a high-fat liquid diet (31.48% fat, 13% protein, and 48.18% carbohydrate, Bio-Serv). Feeds were presented using Liquidiets tubes (Bio-Serve), which permit direct measurement of liquid food consumption. Body mass was recorded weekly. The efficiency of food utilization was calculated as total weight gain (mg) divided by total energy intake (kcal). After 6 wk of the high-fat diet, mice were fasted overnight, anesthetized with methoxyflurane (Jansen Pharmaceuticals, Toronto, ON, Canada), exsanguinated by cardiac puncture, and decapitated. Organs were rapidly removed.
Statistical analysis. Effects of the high-fat diet were analyzed by one-way ANOVA followed by Tukey-Kramer multiple comparison tests using GraphPad InStat (GraphPad Software, San Diego, CA). Other groups were compared using the unpaired two-tailed Student's t-test.
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RESULTS |
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3-adrenergic stimulation: effect on circulating nonesterified fatty acids.
CL-316243 administration caused no obvious behavioral change in mice of either genotype. It resulted in significant increases of nonesterified fatty acids in mice of both genotypes studied (Fig. 2). This increase was less in HSL–/– mice (0.12 ± 0.01 mmol/l) than in HSL+/+ mice (0.33 ± 0.05 mmol/l) (P < 0.01). Glycemia increased to a similar extent in mice of each genotype following injection of either CL-316243 or saline (Fig. 2).
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-Adrenergic and related compounds: effect on lipolysis in isolated adipocytes.
Several compounds that stimulate cAMP all produced similar increases in lipolysis (Fig. 3). Incubation of HSL–/– adipocytes with -adrenergic agents elicited a 2.3-fold increase (P < 0.04) vs. 21.3-fold in HSL+/+ cells. As reported previously (22, 30), basal lipolysis was greater in HSL–/– than in HSL+/+ adipocytes: 58.9 ± 10.3 nmol·10–6 cells·h–1 for HSL–/– vs. 30.3 ± 8.0 nmol·10–6 cells·h–1 for wild-type mice (P < 0.04).
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CO2 and O2 declined with fasting in HSL–/– and normal mice. Respiratory quotients did not differ statistically between HSL–/– mice and controls. This was demonstrated in 8-mo-old females (Fig. 4) and in 3-mo-old females and 7-mo-old males (not shown), both in fed mice and throughout a 48-h fast.
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-adrenergic stimulation.
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Weight gains during 6 wk of a high-fat diet were 2.3 ± 0.9 g for HSL–/–, 10.1 ± 0.6 g for HSL+/–, and 10.6 ± 1.6 g for HSL+/+ mice (Fig. 7). Significant differences were present between HSL–/– and both HSL+/+ and HSL+/– mice (P < 0.01). Of note, HSL–/– mice stopped gaining weight after 2 wk of the fat-rich diet, whereas HSL+/+ and HSL+/– mice gained during the entire experimental period. No statistically significant differences were seen between HSL+/+ and HSL+/– mice (Table 3).
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After a 6-wk high-fat diet, total abdominal fat masses in HSL–/– mice were significantly lower (P < 0.01) than those of HSL+/+ or HSL+/– mice (Table 3). The masses of fat depots (perigonadal, perinephric, and mesenteric) were each smaller in HSL–/– mice than in HSL+/+ or heterozygotes (not shown). Carcass fat content of HSL-deficient mice was 12.22% lower than that of either control (25.87%) and heterozygous mice (26.57%, P < 0.001). After a high-fat diet, mean liver TG content in control and heterozygous mice was greater than that of HSL-deficient mice, but the differences were not statistically significant (Table 3).
Compared with controls, HSL-deficient mice fed a high-fat diet had lower mean levels of nonesterified fatty acids, -hydroxybutyrate, and TG and higher levels of cholesterol, but only the difference of TG level reached significance (P < 0.01) (Table 3).
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DISCUSSION |
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-adrenergic stimulation and fasting, which respectively provide acute and chronic stimulation of lipolysis, and dietary fat loading, which normally induces hyperplasia and hypertrophy of white adipose tissue.
HSL appears to be essential for normal -adrenergic stimulation of lipolysis. FFA levels in HSL–/– mice increase marginally following acute 3-adrenergic stimulation (Fig. 2). In isolated HSL–/– adipocytes, a blunted -adrenergic lipolytic response has previously been reported (22, 30). Figure 3 extends these observations to three -adrenergic agonists and to forskolin (an activator of adenylate cyclase) and dibutyryl- cAMP, a cAMP analog. For free-living animals, the adrenergic response is important for the response to acute danger. The rapid secretion of fatty acids mediated by HSL appears to be an integral part of this circuitry.
Conversely, there is a modest but reproducible increase in lipolysis in HSL–/– cells in response to cAMP-related processes, presumably due to cAMP-dependent, non-HSL compounds. A major candidate is perilipin, a lipid droplet surface protein that is felt to protect droplet TG from lipase activity (30). Phosphorylation of perilipin by protein kinase A is associated with its displacement to the cytoplasm (5, 7). Reduction of perilipin concentration at the lipid droplet surface might indiscriminately expose depot TG to hydrolysis by HSL or other lipase(s).
In HSL-deficient mice, lipolysis increased appropriately throughout the entire fasting period. A similar observation during 24-h fasting was reported in an independently derived HSL–/– mouse strain (22). As judged by calorimetry, the whole body lipolytic rate was normal during 48 h of fasting, even in 8-mo-old HSL–/– mice that had low initial adipose mass (Fig. 4). This suggests that individual HSL-deficient adipocytes can furnish an even greater fasting lipolytic output than those of normal controls. With 48-h fasting, HSL-independent lipolysis persisted to the point of severe depletion of abdominal fat stores. However, the low levels of FFA and of 3HB at the end of a 48-h fast in HSL–/– mice suggest that TG stores are nearly exhausted at this point (Table 2).
The observation of a substantial capacity for HSL-independent lipolysis in white adipose tissue is mirrored in isolated HSL–/– adipocytes, in which fasting lipolysis is substantial, attaining 43% of the maximal rate seen in HSL+/+ adipocytes following -adrenergic stimulation (Fig. 6). In cultured embryonal fibroblasts after in vitro differentiation into adipocytes, Okazaki et al. (21) found a detectable but subnormal response to isoproterenol, similar to that illustrated in Fig. 3. The response was decreased in the presence of H-89, a protein kinase A inhibitor. The same group found an increase in lipolysis in HSL–/– and HSL+/+ cells incubated with tumor necrosis factor-
, although the increase was less in HSL–/– cells. As previously reported in 3T3-L1 cells (26), troglitazone, a peroxisome proliferator-activated receptor-
ligand, inhibited tumor necrosis factor--induced lipolysis in both HSL–/– and HSL+/+ embryonal fibroblasts (21). Thus HSL-independent lipolysis can be increased by tumor necrosis factor-, -adrenergic stimulation, and by fasting. In contrast to other conditions studied in vitro, the changes observed with fasting are greater in HSL–/– than in HSL+/+ cells.
Together, our in vivo and in vitro results show that HSL-independent pathway(s) have the potential to play a major role in normal fasting energy homeostasis. Of note, fasting lipolysis is normal in mice with combined deficiency of 1-, 2-, and 3-receptors (13). Clearly, normal or near-normal fasting lipolysis can occur in the absence of either -adrenergic stimulation or HSL. During fasting in normal mice, the relative roles of HSL- and non-HSL-mediated lipolysis remain to be determined.
Under fed conditions, liver fat content is greater in HSL–/– than in HSL+/+ mice, but fasting reverses this (Table 2). Similar observations have been made in independently derived HSL–/– mice (10). We speculate that, after feeding, the liver may increase its TG content as partial compensation for an inadequate capacity in adipose tissue for fatty acid uptake and TG storage. After fasting, the lower hepatic fat content of HSL–/– vs. HSL+/+ mice may be due to rapid consumption or mobilization of endogenous lipids as well as reduced uptake and availability of fatty acids to liver. Presumably, during fasting in HSL–/– mice, there is increased competition between the liver and nonhepatic tissues for the marginal supplies of fatty acid fuel produced by their small adipose reservoir.
Of note, the fat masses of heterozygous HSL+/– mice were not different from those of normal controls, even after fat loading (Table 3). In contrast, our previous observations suggested that heterozygous HSL+/– mice might be obesity prone (30). The reason for this difference is unclear. The mice studied in our previous report had a high genetic contribution from the 129Sv strain. Our results do not exclude the possibility that, on other genetic backgrounds or under other dietary conditions, HSL haploinsufficiency may exert some effect upon fat mass.
During revision of this article, another publication (11) documented resistance to high-fat diet-induced obesity, using another strain of HSL–/– mice. This strain differs from ours in that the targeted HSL-deficient allele is on a mixed 129/Sv-C57BL6 background. Although the targeted HSL alleles differ between the two strains, complete HSL deficiency is observed in both (11, 30). In HSL–/– mice, intestinal fat absorption was normal, and, as in our mice, a higher daily food intake was noted in relation to body mass. The latter observation contrasts with the selective decrease in fat mass in HSL–/– mice, although lean mass is at least as great in HSL–/– mice as in normal controls. Interestingly, in high-fat-fed mice, these authors noted higher core body temperatures in HSL–/– mice than in controls, suggesting that increased thermogenesis in HSL–/– mice explains obesity resistance in the face of similar fat intakes. Brown adipose tissue hypertrophy is documented in HSL–/– mice (22, 30), although core temperature is normal in HSL–/– mice fed a normal chow diet (22, 30). Upregulation of uncoupling protein-2 was seen in both brown and white adipose tissue of HSL–/– mice (21), as noted in other conditions of increased lipid oxidation or turnover (1, 15, 18, 31).
The limited capacity for hypertrophy of HSL–/– fat tissue likely reflects the adipose tissue pathology observed in these mice (22, 30) but does not explain the fate of the ingested lipid not stored in white adipose depots. These data are consistent with increased energy consumption in HSL–/– mice. Furthermore, from the profile of oxygen consumption in our HSL–/– mice (Fig. 4) we cannot eliminate a small increase compared with that of HSL+/+ mice, which, if present, could reflect important differences in long-term energy homeostasis. Further investigations will be necessary to specifically address this point.
The adipose tissue phenotype of HSL deficiency appears to be progressive, since the fat mass in 8-mo-old mice differed markedly from that of HSL+/+ mice whereas there was no difference at 3 mo of age (Table 1). Fat depots of HSL–/– mice have a reduced storage capacity for TG, particularly with aging (Table 1) and dietary fat loading (Table 3). In free-living mice, this characteristic may be disadvantageous during seasonal and other periods of food shortage. We are testing these notions in a longitudinal study.
In conclusion, adipocyte HSL is the major mediator of -adrenergic lipolysis during acute -adrenergic stimulation and is essential for maintenance of normal white adipose tissue morphology and mass under sedentary conditions (22, 30), aging (Table 1), and dietary fat loading (Fig. 5). Many properties of HSL-independent lipolysis remain to be defined. The components of HSL-independent lipolysis are unknown. The discovery of their identity, and the detailed description of the properties of HSL-independent lipolysis, are important tasks for adipose tissue and obesity research.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
* M. Fortier and S. P. Wang contributed equally to this article. 
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P < 0.05 and 
, HSL+/+; 
, HSL+/–; 
, HSL–/–.