Programming of metabolism by adipokines during development

Following muscle injury, fibro‐adipogenic progenitors (FAPs) are rapidly activated and undergo apoptosis at the resolution stage, which is required for proper muscle regeneration. When excessive FAPs remain, it contributes to fibrotic and fatty infiltration, impairing muscle recovery. Mechanisms controlling FAP apoptosis remain poorly defined. We hypothesized that AMP‐activated protein kinase (AMPK) in FAPs mediates their apoptosis during the muscle regeneration.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/jcsm.13150

AMP‐activated protein kinase inhibition in fibro‐adipogenic progenitors impairs muscle regeneration and increases fibrosis

The prevalence of maternal obesity during pregnancy is associated with the risk of gestational diabetes, preeclampsia, and cardiomyopathy. Environmental factors such as active lifestyles and apelin may lead to beneficial changes. In rats, apelin and exercise (45 to 65% VO2max for 6 to 9 weeks) during pregnancy increase brown adipose tissue (BAT) proteins such as Cidea, Elovl3, UCP1, PRDM16, and PGC-1α in males and females fetuses, while white adipose tissue (WAT) is reduced. In humans and animals, apelin and exercise stimulate the expression of the glucose transporters (GLUT1/2/4) in the muscle and adipose tissue through the PI3K/Akt and AMPK pathways. Hence, exercise and apelin may are known as regulators of energy metabolism and be anti-obesity and anti-diabetic properties. In mice, exercise also creates a short-term hypoxic environment in the pregnant mother, activating HIF-1, VEGF, and VEGFR, and increasing angiogenesis. Exercise and apelin also increase vasodilation, angiogenesis, and suppression of inflammation through the L-arginine/eNOS/NO pathway in humans. Exercise can stimulate the ACE2-Ang-(1-7)-Mas axis in parallel with inhibiting the ACE-Ang II-AT1 pathway. Exercise and apelin seem to prevent preeclampsia through these processes. In rats, moderate-intensity exercise (60 to 70% VO2max for 8 weeks) and apelin/APJ also may prevent pathological hypertrophy in pregnancy by activating the PI3K/Akt/mTOR/p70S6K pathway, PI3k-Akt-ERK1/2-p70S6K pathway, and the anti-inflammatory cytokine IL-10. Since pre-clinical studies have been more on animal models, future research with scientific guidelines should pay more attention to human specimens. In future research, time factors such as the first, second, and third trimesters of pregnancy and the intensity and duration of exercise are important variables that should be considered to determine the optimal intensity and duration of exercise. 

/pdf/possible-roles-of-exercise-and-apelin-against-pregnancy-28sbe4pb.pdf

Possible roles of exercise and apelin against pregnancy complications

Bioconversion of organic waste by insects – A comprehensive review

Excessive accumulation of intermuscular adipose tissue (IMAT) is a common pathological feature in various metabolic and health conditions and can cause muscle atrophy, reduced function, inflammation, insulin resistance, cardiovascular issues, and unhealthy aging. Although IMAT results from fat accumulation in muscle, the mechanisms underlying its onset, development, cellular components, and functions remain unclear. IMAT levels are influenced by several factors, such as changes in the tissue environment, muscle type and origin, extent and duration of trauma, and persistent activation of fibro-adipogenic progenitors (FAPs). FAPs are a diverse and transcriptionally heterogeneous population of stromal cells essential for tissue maintenance, neuromuscular stability, and tissue regeneration. However, in cases of chronic inflammation and pathological conditions, FAPs expand and differentiate into adipocytes, resulting in the development of abnormal and ectopic IMAT. This review discusses the role of FAPs in adipogenesis and how they remodel IMAT. It highlights evidence supporting FAPs and FAP-derived adipocytes as constituents of IMAT, emphasizing their significance in adipose tissue maintenance and development, as well as their involvement in metabolic disorders, chronic pathologies and diseases. We also investigated the intricate molecular pathways and cell interactions governing FAP behavior, adipogenesis, and IMAT accumulation in chronic diseases and muscle deconditioning. Finally, we hypothesize that impaired cellular metabolic flexibility in dysfunctional muscles impacts FAPs, leading to IMAT. A deeper understanding of the biology of IMAT accumulation and the mechanisms regulating FAP behavior and fate are essential for the development of new therapeutic strategies for several debilitating conditions. 

Fibro-adipogenic progenitors in physiological adipogenesis and intermuscular adipose tissue remodeling.

Over the past few decades, genetic selection and refined nutritional management have extensively been used to increase the growth rate and lean meat production of livestock. However, the rapid growth rates of modern breeds are often accompanied by a reduction in intramuscular fat deposition and increased occurrences of muscle abnormalities, impairing meat quality and processing functionality. Early stages of animal development set the long-term growth trajectory of offspring. However, due to the seasonal reproductive cycles of ruminant livestock, gestational nutrient deficiencies caused by seasonal variations, frequent droughts, and unfavorable geological locations negatively affect fetal development and their subsequent production efficiency and meat quality. Therefore, enrolling livestock in nutritional intervention strategies during gestation is effective for improving the body composition and meat quality of the offspring at harvest. These crucial early developmental stages include embryonic, fetal, and postnatal stages, which have stage-specific effects on subsequent offspring development, body composition, and meat quality. This review summarizes contemporary research in the embryonic, fetal, and neonatal development, and the impacts of maternal nutrition on the early development and programming effects on the long-term growth performance of livestock. Understanding the developmental and metabolic characteristics of skeletal muscle, adipose, and fibrotic tissues will facilitate the development of stage-specific nutritional management strategies to optimize production efficiency and meat quality. 

/pdf/stage-specific-nutritional-management-and-developmental-2zukrfo1.pdf

Stage-specific nutritional management and developmental programming to optimize meat production

Maternal exercise (ME) protects against adverse effects of maternal obesity (MO) on fetal development. As a cytokine stimulated by exercise, apelin is elevated due to ME, but its roles in mediating the effects of ME on placental development remain to be defined. Two studies were conducted. In the first study, eighteen female mice were assigned to control (CON), high fat diet-induced obesity (OB) or OB with exercise (OB/Ex) groups (n = 6); in the second study, the same number of female mice were assigned to three groups; CON with PBS injection (CD/PBS), OB/PBS or OB with apelin injection (OB/APN). In the exercise study, daily treadmill exercise during pregnancy significantly elevated the expression of PRDM16 (P < 0.001) which correlated with enhanced oxidative metabolism and mitochondrial biogenesis in placenta (P < 0.05). More importantly, these changes were partially mirrored in the apelin study. Apelin administration upregulated PRDM16 protein level (P < 0.001), mitochondrial biogenesis (P < 0.05), placental nutrient transporter expression (P < 0.001) and placental vascularization (P < 0.01), which were impaired due to MO (P < 0.05). In summary, MO impairs oxidative phosphorylation in the placenta which is improved by ME; apelin administration partially mimics the beneficial effects of exercise on improving placental function, which prevents placental dysfunction due to MO.

Exerkine apelin reverses obesity-associated placental dysfunction by accelerating mitochondrial biogenesis in mice.

Collagen is the main component of connective tissue surrounding adipocytes. Collagen cross-linking affects adipose remodeling, which is crucial for maintaining function and metabolic homeostasis of adipose tissue. However, the effects of obesity on collagen cross-linking and adipose fibrosis remain to be examined. Therefore, the objective of this study was to investigate obesity-induced collagen cross-linking in adipose tissue and explore the underlying mechanisms. We found that obesity increased mature nonreducible collagen cross-linking in white adipose tissue (WAT) of mice, which was associated with inhibition of AMPK, up-regulation of transforming growth factor-β (TGF-β) signaling and the expression of lysyl oxidase (LOX), a key enzyme catalyzing the synthesis of mature cross-linking products. In SVCs and 3T3-L1 adipocytes, AMPK activation by metformin or AICAR inhibited TGF-β1-induced fibrogenesis and expression of LOX, which was further confirmed by ectopic expression of AMPK WT and K45R mutant. Consistently, in vivo, knocking out AMPK increased fibrosis and collagen cross-linking. Our study showed that AMPK downregulation due to obesity increases TGF-β signaling and LOX expression, which enhances adipose fibrosis and collagen cross-linking. Thus, AMPK is a therapeutic target for ameliorating the obesity-induced fibrosis, improving metabolic health of adipose tissue. 

Obesity induces adipose fibrosis and collagen cross-linking through suppressing AMPK and enhancing lysyl oxidase expression.

BACKGROUND
Maternal exercise (ME) improves fetal and offspring muscle development, but mechanisms remain to be established. Since thyroid hormone (TH) is critical for cell differentiation during embryonic development, we hypothesized that ME elevates TH receptor (THR) signaling in embryos, which promotes embryonic myogenesis.


METHODS
Female mice were exercised daily on a treadmill or received a daily TH injection (T3I). Embryos (E12.5) and P19 cells were used for studying effects of TH on embryonic myogenesis. TH levels in serum and embryos after ME or T3I were analyzed. Expression of TH signaling related genes and myogenic genes were assessed. THRα binding to the promoters of myogenic genes was investigated by CHIP-qPCR. A CRISPR/CAS9 plasmid was utilized to knock out THRα in P19 cells.


RESULTS
ME elevated TH levels in both maternal circulation and embryos, which were correlated with enhanced TH signaling and myogenesis. At E12.5, both myogenic determinants (Pax3, Pax7) and myogenic regulatory factors (Myf5, Myod) were upregulated in ME embryos. ME increased THRα content and elevated mRNA expression of TH transporter Slc16a2 and deiodinase Dio2. In addition, the THRα binding to the promoters of Pax3/7 was increased. In P19 embryoid bodies, T3 promoted myogenic differentiation, which was abolished by ablating THRα. Further, maternal daily injection of T3 at a level matching exercised mothers promoted embryonic myogenesis.


CONCLUSIONS
ME promotes TH delivery to the embryos and enhances embryonic myogenesis, which is partially mediated by enhanced TH signaling in ME embryos.

Maternal exercise before and during pregnancy facilitates embryonic myogenesis by enhancing thyroid hormone signaling.

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