IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1–deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis

In addition to its economic value, milk fat is responsible for many of milk's characteristics and can be markedly affected by diet. Diet-induced milk fat depression (MFD) was first described over a century ago and remains a common problem observed under both intensive and extensive management. The biohydrogenation theory established that MFD is caused by an inhibition of mammary synthesis of milk fat by specific fatty acids (FA) produced as intermediates in ruminal biohydrogenation. During MFD, lipogenic capacity and transcription of key lipid synthesis genes in the mammary gland are down-regulated in a coordinated manner. Our investigations have established that expressions of sterol response element-binding protein 1 (SREBP1) and SREBP-activation proteins are down-regulated during MFD. Importantly, key lipogenic enzymes are transcriptionally regulated via SREBP1. Collectively, these results provide strong evidence for SREBP1 as a central signaling pathway in the regulation of mammary FA synthesis. Spot 14 is also down-regulated during MFD, consistent with a lipogenic role for this novel nuclear protein. In addition, SREBP1c and Spot 14 knock-out mice exhibit reduced milk fat similar to the magnitude and pattern of MFD in the cow. Application of molecular biology approaches has provided the latest chapter in the regulation of milk fat synthesis and is reviewed along with a brief background in nutritional regulation of milk fat synthesis in ruminants.

An experiment was conducted to determine the effect of prepartum plane of energy intake on metabolic profiles related to lipid metabolism and health in blood and liver. Primiparous (n=24) and multiparous (n=23) Holsteins were randomly assigned by expected date of parturition to 1 of 3 prepartum energy intakes. A high energy diet [1.62 Mcal of net energy for lactation (NE(L))/kg; 15% crude protein] was fed for either ad libitum intake or restricted intake to supply 150% (OVR) or 80% (RES) of energy requirements for dry cows in late gestation. To limit energy intake to 100% of National Research Council requirements at ad libitum intake, chopped wheat straw was included as 31.8% of dry matter for a control diet (CON; 1.21 Mcal of NE(L)/kg of dry matter; 14.2% crude protein). Regardless of parity group, OVR cows had greater concentrations of glucose, insulin, and leptin in blood prepartum compared with either CON or RES cows; however, dietary effects did not carry over to the postpartum period. Prepartum nonesterified fatty acids (NEFA) were lower in OVR cows compared with either CON or RES cows. Postpartum, however, OVR cows had evidence of greater mobilization of triacylglycerol (TAG) from adipose tissue as NEFA were higher than in CON or RES cows, especially within the first 10 d postpartum. Prepartum β-hydroxybutyrate (BHBA) was not affected by diet before parturition; however, within the first 10 d postpartum, OVR cows had greater BHBA than CON or RES cows. Prepartum diet did not affect liver composition prepartum; however, OVR cows had greater total lipid and TAG concentrations and lower glycogen postpartum than CON or RES cows. Frequency of ketosis and displaced abomasum was greater for OVR cows compared with CON or RES cows postpartum. Controlling or restricting prepartum energy intake yielded metabolic results that were strikingly similar both prepartum and postpartum, independent of parity group. The use of a bulky diet controlled prepartum energy intake in multiparous and primiparous cows, improved metabolic status postpartum, and reduced the incidence of health problems. When metabolic profiles are considered collectively, cows overfed energy prepartum exhibited an "overnutrition syndrome" with characteristics of clinical symptoms displayed by diabetic or obese nonruminant subjects. This syndrome likely contributed to metabolic dysfunction postpartum.

IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1-deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis.

The insulin-like growth factors-I and -II (IGFs) are involved in a wide array of cellular processes such as proliferation, prevention of apoptosis, and differentiation. Most of these effects are mediated by the IGF-I receptor, although at higher IGF concentrations the insulin receptor can also be activated. As the expression of both the IGFs and their receptors is widespread, IGFs are thought to have autocrine/paracrine modes of actions also, particularly during foetal life. The endocrine component of the IGF system is recognised to be important after birth, with IGF-I mediating many of the effects of growth hormone (GH), and linking anabolic processes to nutrient availability. Consideration of ligands and receptors, however, is insufficient to provide a complete understanding of the biology of IGF. This is because IGFs are found in binary complexes of 40-50 kDa with members of a family of IGF-binding proteins (IGFBPs-1 to -6) in all biological fluids. In addition, in postnatal serum, most IGFs are sequestered into ternary complexes of 150 kDa consisting of one molecule each of IGF, IGFBP-3 or IGFBP-5, and acid-labile subunit (ALS). Despite evidence that ALS plays an important role in the biology of circulating IGFs, it has received only limited attention relative to the other components of the IGF system. This review provides an overview on the current knowledge of ALS protein and gene structure, organisation and regulation by hormones, and insights from novel animal models such as the ALS knockout mice.