Yehui Duan

n-6:n-3 PUFA ratio is involved in regulating lipid metabolism and inflammation in pigs.

The objective of the present study was to investigate the optimal dietary n-6:n-3 PUFA ratios that regulate lipid metabolism and inflammation in pigs. A total of ninety-six cross-bred (Large White × Landrace) growing-finishing pigs (73·8 (SEM 1·6) kg) were chosen and fed one of the four isoenergetic diets with n-6:n-3 PUFA ratios of 1:1, 2·5:1, 5:1 and 10:1. The growth performance of pigs fed the diet with an n-6:n-3 PUFA ratio of 5:1 was the best, but the group fed the diet with an n-6:n-3 PUFA ratio of 1:1 had the highest muscle mass and the lowest adipose tissue mass (P< 0·05). The concentrations of IL-6 and IL-1β of pigs fed the diet with an n-6:n-3 PUFA ratio of 1:1 were decreased compared with those of the other groups (P< 0·05). The concentration of adiponectin of pigs fed the diet with an n-6:n-3 PUFA ratio of 1:1 was also markedly decreased, but the concentration of leptin was increased compared with that of the groups fed the diets with n-6:n-3 PUFA ratios of 5:1 and 10:1 (P< 0·05). Additionally, the optimal dietary ratios of n-6:n-3 PUFA of 1:1 and 5:1 markedly suppressed the expression levels of lipid metabolism-related genes and proteins such as phosphoinositide-3-kinase-α, fatty acid transport protein-1 and PPARγ. They also significantly suppressed the expression levels of the inflammatory cytokines IL-1β, TNF-α and IL-6. The results indicated that the optimal n-6:n-3 PUFA ratios of 1:1 and 5:1 exerted beneficial effects on lipid metabolism and inflammatory system, leading to the availability of more energy and nutrients for high performance and homeostatic pathways.

Myokines and adipokines: Involvement in the crosstalk between skeletal muscle and adipose tissue

Skeletal muscle and adipose tissue are the two largest organs in the body. Skeletal muscle is an effector organ, and adipose tissue is an organ that stores energy; in addition, they are endocrine organs that secrete cytokines, namely myokines and adipokines, respectively. Myokines consist of myostatin, interleukin (IL)-8, IL-15, irisin, fibroblast growth factor 21, and myonectin; adipokines include leptin, adiponectin, resistin, chemerin, and visfatin. Furthermore, certain cytokines, such as IL-6 and tumor necrosis factor-α, are released by both skeletal muscle and adipose tissue and exhibit a bioactive effect; thus, they are called adipo-myokines. Recently, novel myokines or adipokines were identified through the secretomic technique, which has expanded our knowledge on the previously unknown functions of skeletal muscle and adipose tissue and provide a new avenue of investigation for obesity treatment or animal production. This review focuses on the roles of and crosstalk between myokines and adipokines in skeletal muscle and adipose tissue that modulate the molecular events in the metabolic homeostasis of the whole body.

Myostatin regulates preadipocyte differentiation and lipid metabolism of adipocyte via ERK1/2

Myostatin is known as an inhibitor of muscle development, but its role in adipogenesis and lipid metabolism is still unclear, especially the underlying mechanisms. Here, we demonstrated that myostatin inhibited 3T3‐L1 preadipocyte differentiation into adipocyte by suppressing C/EBPα (CCAAT/enhancer‐binding protein α) and PPARα (peroxisome‐proliferator‐activated receptor α), also activated ERK1/2 (extracellular‐signal‐regulated kinase 1/2). Furthermore, myostatin enhanced the phosphorylation of HSL (hormone‐sensitive lipase) and ACC (acetyl‐CoA carboxylase) in fully differentiated adipocytes, as well as ERK1/2. Besides, we noted that myostatin markedly raised the levels of leptin and adiponectin release and mRNA expression during preadipocyte differentiation, but the levels were inhibited by myostatin treatments in fully differentiated adipocytes. These results suggested that myostatin suppressed 3T3‐L1 preadipocyte differentiation and regulated lipid metabolism of mature adipocyte, in part, via activation of ERK1/2 signalling pathway.

Key mediators of intracellular amino acids signaling to mTORC1 activation.

Mammalian target of rapamycin complex 1 (mTORC1) is activated by amino acids to promote cell growth via protein synthesis. Specifically, Ras-related guanosine triphosphatases (Rag GTPases) are activated by amino acids, and then translocate mTORC1 to the surface of late endosomes and lysosomes. Ras homolog enriched in brain (Rheb) resides on this surface and directly activates mTORC1. Apart from the presence of intracellular amino acids, Rag GTPases and Rheb, other mediators involved in intracellular amino acid signaling to mTORC1 activation include human vacuolar sorting protein-34 (hVps34) and mitogen-activating protein kinase kinase kinase kinase-3 (MAP4K3). Those molecular links between mTORC1 and its mediators form a complicate signaling network that controls cellular growth, proliferation, and metabolism. Moreover, it is speculated that amino acid signaling to mTORC1 may start from the lysosomal lumen. In this review, we discussed the function of these mediators in mTORC1 pathway and how these mediators are regulated by amino acids in details.

Leucine in Obesity: Therapeutic Prospects

Obesity develops from an imbalance of energy homeostasis and is associated with chronic low-grade inflammation in white adipose tissues (WAT). Inflammation is involved in the pathophysiology of many obesity-induced disorders including insulin resistance and diabetes. Increasing evidence has shown that dietary leucine supplementation positively affects the parameters associated with obesity and obesity-related metabolic disorders. The beneficial effects include increased loss of body weight, reduced WAT inflammation, improved lipid and glucose metabolism, enhanced mitochondrial function, and preserved lean body mass. Although these beneficial effects have not been clearly established, dietary leucine supplementation, either alone or as part of a therapeutic regimen, may be a good nutritional tool in the prevention and management of obesity and obesity-induced metabolic disorders.

Metabolic control of myofibers: promising therapeutic target for obesity and type 2 diabetes

Mammalian skeletal muscles are composed of two major fibre types (I and II) that differ in terms of size, metabolism and contractile properties. In general, slow‐twitch type I fibres are rich in mitochondria and have a greater insulin sensitivity than fast‐twitch type II skeletal muscles. Although not widely appreciated, a forced induction of the slow skeletal muscle phenotype may inhibit the progress of obesity and diabetes. This potentially forms the basis for targeting slow/oxidative myofibers in the treatment of obesity. In this context, a better understanding of the molecular basis of fibre‐type specification and plasticity may help to identify potential therapeutic targets for obesity and diabetes.

Signaling Pathways Related to Protein Synthesis and Amino Acid Concentration in Pig Skeletal Muscles Depend on the Dietary Protein Level, Genotype and Developmental Stages

Muscle growth is regulated by the homeostatic balance of the biosynthesis and degradation of muscle proteins. To elucidate the molecular interactions among diet, pig genotype, and physiological stage, we examined the effect of dietary protein concentration, pig genotype, and physiological stages on amino acid (AA) pools, protein deposition, and related signaling pathways in different types of skeletal muscles. The study used 48 Landrace pigs and 48 pure-bred Bama mini-pigs assigned to each of 2 dietary treatments: lower/GB (Chinese conventional diet)- or higher/NRC (National Research Council)-protein diet. Diets were fed from 5 weeks of age to respective market weights of each genotype. Samples of biceps femoris muscle (BFM, type I) and longissimus dorsi muscle (LDM, type II) were collected at nursery, growing, and finishing phases according to the physiological stage of each genotype, to determine the AA concentrations, mRNA levels for growth-related genes in muscles, and protein abundances of mechanistic target of rapamycin (mTOR) signaling pathway. Our data showed that the concentrations of most AAs in LDM and BFM of pigs increased (P<0.05) gradually with increasing age. Bama mini-pigs had generally higher (P<0.05) muscle concentrations of flavor-related AA, including Met, Phe, Tyr, Pro, and Ser, compared with Landrace pigs. The mRNA levels for myogenic determining factor, myogenin, myocyte-specific enhancer binding factor 2 A, and myostatin of Bama mini-pigs were higher (P<0.05) than those of Landrace pigs, while total and phosphorylated protein levels for protein kinase B, mTOR, and p70 ribosomal protein S6 kinases (p70S6K), and ratios of p-mTOR/mTOR, p-AKT/AKT, and p-p70S6K/p70S6K were lower (P<0.05). There was a significant pig genotype-dependent effect of dietary protein on the levels for mTOR and p70S6K. When compared with the higher protein-NRC diet, the lower protein-GB diet increased (P<0.05) the levels for mTOR and p70S6K in Bama mini-pigs, but repressed (P<0.05) the level for p70S6K in Landrace pigs. The higher protein-NRC diet increased ratio of p-mTOR/mTOR in Landrace pigs. These findings indicated that the dynamic consequences of AA profile and protein deposition in muscle tissues are the concerted effort of distinctive genotype, nutrient status, age, and muscle type. Our results provide valuable information for animal feeding strategy.

β-Hydroxy-β-methylbutyrate, mitochondrial biogenesis, and skeletal muscle health

The metabolic roles of mitochondria go far beyond serving exclusively as the major producer of ATP in tissues and cells. Evidence has shown that mitochondria may function as a key regulator of skeletal muscle fiber types and overall well-being. Maintaining skeletal muscle mitochondrial content and function is important for sustaining health throughout the lifespan. Of great importance, β-hydroxy-β-methylbutyrate (HMB, a metabolite of l-leucine) has been proposed to enhance the protein deposition and efficiency of mitochondrial biogenesis in skeletal muscle, as well as muscle strength in both exercise and clinical settings. Specifically, dietary supplementation with HMB increases the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), which represents an upstream inducer of genes of mitochondrial metabolism, coordinates the expression of both nuclear- and mitochondrion-encoded genes in mitochondrial biogenesis. Additionally, PGC-1α plays a key role in the transformation of skeletal muscle fiber type, leading to a shift toward type I muscle fibers that are rich in mitochondria and have a high capacity for oxidative metabolism. As a nitrogen-free metabolite, HMB holds great promise to improve skeletal muscle mass and function, as well as whole-body health and well-being of animals and humans.

Myokine interleukin-15 expression profile is different in suckling and weaning piglets

Interleukin-15 (IL-15) is a cytokine highly expressed in skeletal muscle. The objective of the present study was to investigate the development of muscle IL-15 expression in suckling piglets and in early weaning piglets (day 14) at each level, that is, mRNA, protein, and secretion. Eight litters (eight piglets per litter) of newborn healthy piglets (Large × White × Landrace) with a similar initial weight (1618.0 ± 140.1 g) were chosen and divided into two groups. Group one used suckling piglets that were killed, respectively, at days 1, 7, 14, 21, and group two used early (day 14) weaning piglets that were killed respectively, at days 15, 17, 19, 21. In group one, IL-15 gene expression levels increased significantly (P < 0.05) along with increased body weight over time. IL-15 protein expression levels in piglets at day 21 of age were higher (P < 0.05) than those in piglets at other ages, and there was no difference (P > 0.05) among piglets at other ages. These findings indicated that increased IL-15 mRNA expression did not result in a corresponding increase of its protein expression. In group two, which used early weaning piglets from days 15–19, IL-15 mRNA and protein expression levels increased constantly (P < 0.05) and were higher (P < 0.05) than those in suckling piglets. Moreover, there was no gain of body weight (P > 0.05) compared with suckling piglets at day 14 of age. However, IL-15 protein expression levels in early weaning piglets at day 21 of age dropped significantly (P < 0.05) to the levels as suckling piglets at day 21 of age, while body weight increased (P < 0.05) markedly to the levels as suckling piglets at day 21 of age. In both groups, the serum IL-15 levels of piglets decreased significantly (P < 0.01) over time. Taken together, our results indicate that IL-15 expression differs in suckling piglets and in weaning piglets. It is speculated that IL-15 may play an important role in counteracting the effects of early weaning stress.

Interleukin-15 in obesity and metabolic dysfunction: current understanding and future perspectives: Interleukin-15 and obesity

Obesity rises rapidly and is a major health concern for modern people. Importantly, it is a major risk factor in the development of numerous chronic diseases such as type 2 diabetes mellitus (T2DM). Recently, interleukin (IL)‐15 has attracted considerable attention as a potential regulator for the prevention and/or treatment of obesity and T2DM. The beneficial effects include increased loss of fat mass and body weight, improved lipid and glucose metabolism, reduced white adipose tissue inflammation, enhanced mitochondrial function, alterations in the composition of muscle fibres and gut bacterial and attenuated endoplasmic reticulum stress. Although these beneficial effects are somewhat controversial, IL‐15, exogenously delivered or endogenously produced, may be a promising target in the prevention and treatment of obesity and T2DM.