miR-133a Regulates Adipocyte Browning In Vivo.

Prdm16 determines the bidirectional fate switch of skeletal muscle/brown adipose tissue (BAT) and regulates the thermogenic gene program of subcutaneous white adipose tissue (SAT) in mice. Here we show that miR-133a, a microRNA that is expressed in both BAT and SATs, directly targets the 3′ UTR of Prdm16. The expression of miR-133a dramatically decreases along the commitment and differentiation of brown preadipocytes, accompanied by the upregulation of Prdm16. Overexpression of miR-133a in BAT and SAT cells significantly inhibits, and conversely inhibition of miR-133a upregulates, Prdm16 and brown adipogenesis. More importantly, double knockout of miR-133a1 and miR-133a2 in mice leads to elevations of the brown and thermogenic gene programs in SAT. Even 75% deletion of miR-133a (a1−/−a2+/−) genes results in browning of SAT, manifested by the appearance of numerous multilocular UCP1-expressing adipocytes within SAT. Additionally, compared to wildtype mice, miR-133a1−/−a2+/− mice exhibit increased insulin sensitivity and glucose tolerance, and activate the thermogenic gene program more robustly upon cold exposure. These results together elucidate a crucial role of miR-133a in the regulation of adipocyte browning in vivo

Notch signaling regulates adipose browning and energy metabolism

Beige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet-induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes

Fat infiltration in skeletal muscle: Influential triggers and regulatory mechanism

Summary: Fat infiltration in skeletal muscle (also known as myosteatosis) is now recognized as a distinct disease from sarcopenia and is directly related to declining muscle capacity. Hence, understanding the origins and regulatory mechanisms of fat infiltration is vital for maintaining skeletal muscle development and improving human health. In this article, we summarized the triggering factors such as aging, metabolic diseases and metabolic syndromes, nonmetabolic diseases, and muscle injury that all induce fat infiltration in skeletal muscle. We discussed recent advances on the cellular origins of fat infiltration and found several cell types including myogenic cells and non-myogenic cells that contribute to myosteatosis. Furthermore, we reviewed the molecular regulatory mechanism, detection methods, and intervention strategies of fat infiltration in skeletal muscle. Based on the current findings, our review will provide new insight into regulating function and lipid metabolism of skeletal muscle and treating muscle-related diseases

Lipo-nutritional quality of pork: The lipid composition, regulation, and molecular mechanisms of fatty acid deposition

Pork is one of the main meats consumed by people, and its nutritional value is closely related to human health. The lipid deposition and composition of pork not only affect the sensory quality but also determine the nutritional quality of pork. The lipids in pork include triglycerides (TAG) and a small amount of cholesterol and phospholipids. TAG are the main lipids in skeletal muscle fat, which is divided into intermuscular fat and intramuscular fat (IMF). In addition to TAG, IMF also contains phospholipids, which are important factors affecting pork flavour. There are three types of fatty acids in TAG: saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA). PUFA, such as n-3 PUFA, have a beneficial effect on health, including the regulation of whole-body energy metabolism and protection against cardiovascular diseases. Therefore, regulating lipid deposition, especially the fatty acid composition, in pork is important for improving the nutritional quality for human health. Notably, several strategies, such as breeding, environmental control, and the nutritional regulation of lipid composition and deposition in pork, have been studied. More recently, faecal transplantation, molecular design breeding and non-coding RNA have been studied and proven useful for regulating lipid deposition in pigs. In this review, we mainly summarized and discussed the research findings to date on the lipid composition and regulation mechanisms of fatty acid deposition and provide new insights into efficient means of improving the lipid composition and lipo-nutritional quality of pork

The Effect of Rearing Conditions on Carcass Traits, Meat Quality and the Compositions of Fatty Acid and Amino Acid of LTL in Heigai Pigs

The present study evaluates the influence of captivity and grazing rearing conditions on the carcass traits, meat quality and fatty acid profiles of Heigai pigs. Ten Heigai pigs with market weight were randomly selected from both the indoor feeding farm and outdoor grazing farm groups (FF and GF; five pigs per group) for measuring production performance. The results showed that the shear force of longissimus thoracis et lumborum (LTL) in the GF group tended to increase (p = 0.06), and triglyceride and cholesterol contents in LTL and psoas major muscle (PMM) of the GF group significantly increased and decreased, respectively (p < 0.05). The proportion of saturated fatty acids (SFA) was significantly increased (p < 0.05) in the GF group. Meanwhile, the ratios of unsaturated fatty acid (UFA), polyunsaturated fatty acid (PUFA), monounsaturated fatty acid (MUFA) and the content of flavor amino acid of the LTL in the GF group were significantly decreased (p < 0.05). The GF upregulated the expression of MyHC-IIb and lipogenic genes, such as GLUT4 and LPL (p < 0.05), in LTL and PMM, but downregulated the expression of MyHC-I, MyHC-IIa, PPARγ and leptin (p < 0.05). In conclusion, these results suggested that the different rearing conditions can alter the meat qualities by mediating the muscle fiber type and lipid metabolism of Heigai pigs

Metformin Protects against LPS-Induced Intestinal Barrier Dysfunction by Activating AMPK Pathway

Metformin not only regulates energy metabolism but also participates in many cellular processes. In this study, we investigated the effect of metformin on lipopolysaccharide (LPS)-induced intestinal barrier damage. We found that LPS treatment decreased the expression of tight junction proteins and caused a proinflammatory response and oxidative stress in the intestine. Interestingly, metformin treatments attenuated LPS-induced intestinal barrier damage, inflammation, and oxidative stress. We found that metformin improved the expression of intestinal tight junction proteins (ZO1, occludin, and Claudin1) that were reduced by LPS stimulation. Moreover, metformin alleviated LPS-induced NF-κB phosphorylation, promoted Nrf2 nuclear translocation, and increased the expression of the antioxidative genes (HO-1 and NQO-1), leading to reduced intestinal ROS content. Mechanistically, we found that metformin protects against LPS-induced intestinal barrier dysfunction by activating AMPK. These results reveal the potential of metformin as an effective therapy for treating intestinal diseases

Single-nucleus and bulk RNA sequencing reveal cellular and transcriptional mechanisms underlying lipid dynamics in high marbled pork

Abstract Pork is the most consumed meat in the world, and its quality is associated with human health. Intramuscular fat (IMF) deposition (also called marbling) is a key factor positively correlated with various quality traits and lipo-nutritional values of meat. However, the cell dynamics and transcriptional programs underlying lipid deposition in highly marbled meat are still unclear. Here, we used Laiwu pigs with high (HLW) or low (LLW) IMF contents to explore the cellular and transcriptional mechanisms underlying lipid deposition in highly-marbled pork by single-nucleus RNA sequencing (snRNA-seq) and bulk RNA sequencing. The HLW group had higher IMF contents but less drip loss than the LLW group. Lipidomics results revelled the changes of overall lipid classes composition (e.g., glycerolipids including triglycerides, diglycerides, and monoglycerides; sphingolipids including ceramides and monohexose ceramide significantly increased) between HLW and LLW groups. SnRNA-seq revealed nine distinct cell clusters, and the HLW group had a higher percentage of adipocytes (1.40% vs. 0.17%) than the LLW group. We identified 3 subpopulations of adipocytes, including PDE4D+/PDE7B+ (in HLW and LLW), DGAT2+/SCD+ (mostly in HLW) and FABP5+/SIAH1+ cells (mostly in HLW). Moreover, we showed that fibro/adipogenic progenitors could differentiate into IMF cells and contribute to 43.35% of adipocytes in mice. In addition, RNA-seq revealed different genes involved in lipid metabolism and fatty acid elongation. Our study provides new insights into the cellular and molecular signatures of marbling formation; such knowledge may facilitate the development of new strategies to increase IMF deposition and the lipo-nutritional quality of high marbled pork

Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1

Brown adipose tissues (BAT) burn lipids to generate heat through uncoupled respiration, thus representing a powerful target to counteract lipid accumulation and obesity. The tumor suppressor liver kinase b1 (Lkb1) is a key regulator of cellular energy metabolism; and adipocyte-specific knockout of Lkb1 (Ad-Lkb1 KO) leads to the expansion of BAT, improvements in systemic metabolism and resistance to obesity in young mice. Here we report the unexpected finding that the Ad-Lkb1 KO mice develop hindlimb paralysis at mid-age. Gene expression analyses indicate that Lkb1 KO upregulates the expression of inflammatory cytokines in interscapular BAT and epineurial brown adipocytes surrounding the sciatic nerve. This is followed by peripheral neuropathy characterized by infiltration of macrophages into the sciatic nerve, axon degeneration, reduced nerve conductance, and hindlimb paralysis. Mechanistically, Lkb1 KO reduces AMPK phosphorylation and amplifies mammalian target-of-rapamycin (mTOR)-dependent inflammatory signaling specifically in BAT but not WAT. Importantly, pharmacological or genetic inhibition of mTOR ameliorates inflammation and prevents paralysis. These results demonstrate that BAT inflammation is linked to peripheral neuropathy

miR-133a and miR-128 target the 3′ UTR of Prdm16 in HEK293 cells.

<p>(A–B) qPCR analysis of miR-1, miR-206, miR-133a, miR-128 and Prdm16, for asWAT and ingWAT of wildtype mice. (C) Putative miRNA target sites within the 3 ′UTR of <i>Prdm16</i>. (D–E) Luciferase assay. Plasmids carrying luciferase gene linked to 3′ UTR of <i>Prdm16</i> were cotransfected to HEK293 cells, along with control miRNA, miR-133a (D) or miR-128 (E) at indicated doses. Luciferase activity was measure at 48h post-transfection and normalized. N = 4, *P<0.05, **P<0.01.</p