Previous research showed that neonatal pigs respond to decreases in energy density of liquid diets with increased feed intake, resulting in similar performance to pigs fed a more energy-dense diet. The objective of this experiment was to determine whether a high- (25%, HF) or low-fat (2%, LF) liquid diet would affect nutrient accretion rate and select proteins involved in energy homeostasis and protein synthesis in early weaned pigs. Ninety-six pigs, with an initial BW of 3,637 +/- 85 g, were weaned from the sow at 10 d of age and utilized in a randomized complete block design. Pigs were blocked by BW and then assigned to pens (8 pigs/pen). Diets were formulated to provide a constant AA:ME ratio and were fed for 10 d. Pigs were killed at 10, 15, and 20 d of age, at which time blood and LM were collected, and carcasses were prepared for body composition analysis. Blood was analyzed for plasma urea nitrogen (PUN) and NEFA. Longissimus dorsi was analyzed via western immunoblot for mammalian target of rapamycin (mTOR) and adenosine 5' monophosphate-activated protein kinase (AMPK) phosphorylation. Pigs gained 347 +/- 11 g/d, which resulted in an ending BW of 6,858 +/- 135 g, regardless of dietary treatment (P > 0.49). Pigs fed the LF diet consumed 25% more milk than pigs fed the HF diet (2,853 +/- 86 vs. 2,269 +/- 79 g dry feed.pen(-1).d(-1); P < 0.01), which resulted in similar calculated ME intakes between dietary treatments (9.9 +/- 0.2 vs. 10.5 +/- 0.2 Mcal.pen(-1).d(-1); P > 0.5). Feed conversion (G:F) was 24% greater in HF-fed compared with LF-fed pigs (P < 0.01). Circulating NEFA (40 +/- 14 vs. 138 +/- 21 microEq/L; P < 0.01) and PUN (3.0 +/- 0.6 vs. 17.7 +/- 0.8 mM; P < 0.01) concentrations were less in LF pigs compared with HF pigs after 10 d of dietary treatments. Pigs consuming the LF diet had a 21% increase in protein accretion (50.5 +/- 2.8 vs. 61.2 +/- 2.8 g/d; P < 0.04) and a 71% reduced lipid accretion rate (28.8 +/- 2.0 vs. 8.3 +/- 2.3 g/d; P < 0.001). Phosphorylation of AMPK was 29% less (P < 0.03) in LF pigs compared with HF pigs, whereas mTOR phosphorylation was increased by 37% in LF pigs (P < 0.01). We conclude that feeding a LF liquid diet to pigs weaned from the sow at 10 d of age increases feed intake to regulate energy intake while maintaining growth performance. In addition, 10-d-old pigs consuming a liquid LF diet have increased protein deposition by a mechanism mediated through AMPK and mTOR.