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Introduction Nutrient restriction engages a variety of metabolic and behavioral adaptations, and in the case of energy restriction, these adaptations are well described as including alterations in feeding behavior, energy [...], Enhanced fibroblast growth factor 21 (FGF21) production and circulation has been linked to the metabolic adaptation to starvation. Here, we demonstrated that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction. Circulating FGF21 was increased 10-fold in mice and rats fed a low-protein (LP) diet. In these animals, liver Fgf21 expression was increased within 24 hours of reduced protein intake. In humans, circulating FGF21 levels increased dramatically following 28 days on a LP diet. LP-induced increases in FGF21 were associated with increased phosphorylation of eukaryotic initiation factor 2a (eIF2α) in the liver, and both baseline and LP- induced serum FGF21 levels were reduced in mice lacking the eIF2α kinase general control nonderepressible 2 (GCN2). Finally, while protein restriction altered food intake, energy expenditure, and body weight gain in WT mice, FGF21-deficient animals did not exhibit these changes in response to a LP diet. These and other data demonstrate that reduced protein intake underlies the increase in circulating FGF21 in response to starvation and a ketogenic diet and that FGF21 is required for behavioral and metabolic responses to protein restriction. FGF21 therefore represents an endocrine signal of protein restriction, which acts to coordinate metabolism and growth during periods of reduced protein intake.

Dietary methionine restriction (MR) limits fat deposition and decreases plasma leptin, while increasing food consumption, total energy expenditure (EE), plasma adiponectin, and expression of uncoupling protein 1 (UCP1) in brown and white adipose tissue (BAT and WAT). [beta]adrenergic receptors ([beta] ]AR) serve as conduits for sympathetic input to adipose tissue, but their role in mediating the effects of MR on energy homeostasis is unclear. Energy intake, weight, and adiposity were modestly higher in [[beta].sub.3][AR.sup. ]/mice on the Control diet compared with wild ]]type (WT) mice, but the hyperphagic response to the MR diet and the reduction in fat deposition did not differ between the genotypes. The absence of [[beta].sub.3]ARs also did not diminish the ability of MR to increase total EE and plasma adiponectin or decrease leptin mRNA, but it did block the MR ]dependent increase in UCP1 mRNA in BAT but not WAT. In a further study, propranolol was used to antagonize remaining [beta]adrenergic input ([[beta].sub.1] and [[beta].sub.2]ARs) in [[beta].sub.3][AR.sup./] mice, and this treatment blocked >50% of the MR ]induced increase in total EE and UCP1 induction in both BAT and WAT. We conclude that signaling through [beta]adrenergic receptors is a component of the mechanism used by dietary MR to increase EE, and that [[beta].sub.1] and [[beta].sub.2]ARs are able to substitute for [[beta].sub.3] ]ARs in mediating the effect of dietary MR on EE. These findings are consistent with the involvement of both UCP1 dependent and]independent mechanisms in the physiological re sponses affecting energy balance that are produced by dietary MR. energy expenditure; metabolic efficiency; futile cycles; adipose tissue; dietary restriction; leptin; adiponectin; oxidative metabolism; uncoupling doi: 10.1152/ajpregu.00838.2009.

Dietary methionine restriction (MR) is a mimetic of chronic dietary restriction (DR) in the sense that MR increases rodent longevity, but without food restriction. We report here that MR also persistently increases total energy expenditure (EE) and limits fat deposition despite increasing weight-specific food consumption. In Fischer 344 (F344) rats consuming control or MR diets for 3, 9, and 20 mo, mean EE was 1.5-fold higher in MR vs. control rats, primarily due to higher EE during the night at all ages. The day-to-night transition produced a twofold higher heat increment of feeding (3.0[degrees]C vs. 1.5[degrees]C) in MR vs. controls and an exaggerated increase in respiratory quotient (RQ) to values greater than 1, indicative of the interconversion of glucose to lipid by de novo lipogenesis. The simultaneous inhibition of glucose utilization and shift to fat oxidation during the day was also more complete in MR (RQ ~0.75) vs. controls (RQ ~0.85). Dietary MR produced a rapid and persistent increase in uncoupling protein 1 expression in brown (BAT) and white adipose tissue (WAT) in conjunction with decreased leptin and increased adiponectin levels in serum, suggesting that remodeling of the metabolic and endocrine function of adipose tissue may have an important role in the overall increase in EE. We conclude that the hyperphagic response to dietary MR is matched to a coordinated increase in uncoupled respiration, suggesting the engagement of a nutrient-sensing mechanism, which compensates for limited methionine through integrated effects on energy homeostasis. energy expenditure; metabolic efficiency; oxidative metabolism; futile cycles; adipose tissue; dietary restriction doi: 10.1152/ajpregu.00837.2009.

Chimeric G proteins made by replacing the COOH-terminal heptapeptide of [G.sub.[alpha]]q with the COOH-terminal heptapeptide of [G.sub.[alpha]]s or [G.sub.[alpha]]i were used to assess the relative coupling of [[beta].sub.3]-adrenergic receptor ([[beta].sub.3]-AR) splice variants ([[beta].sub.3A] and [[beta].sub.3B]) to [G.sub.[alpha]]s and [G.sub.[alpha]]i. The [G.sub.[alpha]]q/s and [G.sub.[alpha]]q/i chimeras transformed the response to receptor activation from regulation of adenylyl cyclase to mobilization of intracellular calcium ([Ca.sup.2+]i). Complementary high-throughput and single-cell approaches were used to evaluate agonist-induced coupling of the receptor to the G protein chimeras. In cells stably transformed with rat [[beta].sub.3]-AR, transfected with the G protein chimeras, and evaluated using a scanning fluorometer, [[beta].sub.3]-AR-induced coupling to [G.sub.[alpha]]q/s produced a rapid eightfold increase in [Ca.sup.2+]i followed by a slow decay to levels 25% above baseline. [G.sub.[alpha]]q/i also linked rat [[beta].sub.3]-AR to mobilization of [Ca.sup.2+]i in a similar time- and agonist-dependent manner, but the net 2.5-fold increase in [Ca.sup.2+]i was only 30% of the response obtained with [G.sub.[alpha]]q/s. Activation of the rat [[beta].sub.3]-AR also increased GTP binding to endogenous [G.sub.[alpha]]i threefold in membranes from CHO cells stably transformed with the receptor. A complementary single-cell imaging approach was used to assess the relative coupling of mouse [[beta].sub.3A]- and [[beta].sub.3B]-AR to [G.sub.[alpha]]i under conditions established to produce equivalent agonist-dependent coupling of the receptor splice variants to [G.sub.[alpha]]q/s and to increases in intracellular cAMP through endogenous [G.sub.[alpha]]s. The [[beta].sub.3A]- and [[beta].sub.3B]-AR coupled equivalently to [G.sub.[alpha]]q/i, but the temporal patterns of [Ca.sup.2+]i mobilization indicated that coupling was significantly less efficient than coupling to [G.sub.[alpha]]q/s. Collectively, these findings indicate less efficient but equivalent coupling of [[beta].sub.3A]- and [[beta].sub.3B]-AR to [G.sub.[alpha]]i vs. [G.sub.[alpha]]s and suggest that differential expression of the splice variants would not produce local differences in signaling networks linked to [[beta].sub.3]-AR activation. [beta]-adrenergic receptor; G proteins; cyclic adenosine monophosphate; signaling plasticity

Siberian hamsters (Phodopus sungorus) exhibit a naturally occurring, reversible seasonal obesity with body fat peaking in long 'summerlike' days (LDs) and reaching a nadir in short 'winterlike' days (SDs). These SD-induced decreases in adiposity are mediated largely via sympathetic nervous system (SNS) innervation of white adipose tissue (WAT), as indicated by increased WAT norepinephrine (NE) turnover. We examined whether SDs also increase sensitivity to NE-stimulated lipolysis. This was accomplished by measuring NE- and [[beta].sub.3]-adrenoceptor ([[beta].sub.3]-AR) agonist (BRL-37344)-induced lipolysis (glycerol release) as well as NE-induced cAMP accumulation by inguinal, epididymal, and retroperitoneal WAT (IWAT, EWAT, and RWAT) in isolated adipocytes of LD- and SD-housed hamsters. SDs increased potency/efficacy of NE-triggered lipolysis in a temporally and fat pad-specific manner. Thus when WAT pad mass decreased most rapidly (5 wk of SDs), potency (sensitivity/E[C.sub.50]) and efficacy (maximal response asymptote) of NE-stimulated lipolysis were increased for all WAT pads and also at 10 wk for IWAT compared with their LD counterparts. SD enhancement of lipolysis was similar for NE and BRL-37344 in IWAT adipocytes. These results, coupled with our previous demonstration that SDs upregulate WAT [[beta].sub.3]-AR mRNA expression, suggest that increased [[beta].sub.3]-ARs mediated the SD-induced increased NE sensitivity. NE-stimulated adipocyte accumulation of cAMP was greater after 5 wk of SDs for IWAT and EWAT and after 10 wk of SDs for IWAT compared with LDs, with no photoperiod effect for RWAT. Therefore, the SD-induced increase in SNS drive to WAT and increased sensitivity to this drive may work together to increase lipolysis in SDs. lipolysis; body fat; BRL-37344; body weight; sympathetic

Obesity-prone (AKR/J) and obesity-resistant (SWR/J) mice were weaned onto low (LF) or high fat (HF) diets to identify adaptive changes in adipocyte gene expression that are associated with differences between the strains in fat deposition. Food consumption was monitored at weekly intervals and all mice were evaluated after consuming their respective diets for 4 wk for analysis of mRNA levels of selected metabolic genes. Despite similar food consumption, body weight and fat deposition were significantly greater in AKR/J than in SWR/J mice, and this difference was greatly accentuated by the HF diet. The HF diet produced distinct differences between strains in gene expression patterns among fat depots. In AKR/J mice, UCP1 mRNA was decreased 10-fold in interscapular brown adipose tissue (BAT) and four- to fivefold in retroperitoneal and inguinal white adipose tissue (WAT). The HF diet also decreased PGC-1 and [beta]3-adrenergic receptor mRNA by two- and ninefold in BAT from AKR/J mice. In contrast, the HF diet either increased uncoupling protein (UCP)1 in BAT or had no effect on expression of these genes in adipose tissues from SWR/J mice. UCP2 mRNA was fourfold higher in WAT from AKR/J compared with SWR/J mice and increased by an additional twofold in WAT from AKR/J mice fed the HF diet. UCP2 was unaffected by diet in SWR/J mice. These studies show that the diet-induced obesity of AKR/J mice is characterized by increased metabolic efficiency and is associated with changes in adipocyte gene expression that limit the adaptive thermogenic response to increased energy density. KEY WORDS: * uncoupling proteins * adipose tissue * adaptive thermogenesis * mice

Photoperiodic regulation of gene expression in brown and white adipose tissue of Siberian hamsters (Phodopus sungorus). Am J Physiol Regulatory Integrative Comp Physiol 282: R114-R121, 2002.--Siberian hamsters exhibit seasonal fluctuations in white adipose tissue (WAT) mass, with peaks in long 'summerlike' days (LDs) and nadirs in short 'winterlike' days (SDs). These responses can be mimicked in the laboratory after transfer from LDs to SDs. The purpose of the present study was to test whether changes in WAT and brown adipose tissue (BAT) gene expression that are mediated by the sympathetic nervous system in other obesity models are also associated with seasonal adiposity changes in Siberian hamsters. SDs decreased WAT mass and leptin mRNA, increased WAT [[beta].sub.3]-adrenoceptor mRNA, and induced retroperitoneal WAT uncoupling protein-1 mRNA (the latter measured by RT-PCR, others measured by ribonuclease protection assay) while increasing BAT uncoupling protein-1 and peroxisome proliferator-activated receptor-[gamma] coactivator-1 mRNAs. These effects were not due to SD-induced gonadal regression and largely occurred before the usual SD-induced decreases in food intake. Thus the SD-induced decreased adiposity of Siberian hamsters may be due to a coordinated suite of WAT and BAT gene transcription changes ultimately increasing lipid mobilization and utilization. uncoupling protein; peroxisome proliferator-activated receptor-[gamma] coactivator-1; photoperiod; body fat; leptin; sympathetic nervous system; adrenergic

A study was conducted to validate the hypothesis that states that the translocation of G proteins of the G(sub q/11)alpha family in purified plasma membranes and whole Madin-Darby canine kidney cells is influenced by bradykinin (BK). Results revealed that the G proteins of the G(sub q/11)alpha translocated from the plasma membrane to another intracellular compartment in response to the stimulation of BK. The physiological reason for the translocation is yet to be determined.