Adipocyte-Specific Expression of PGC1α Promotes Adipocyte Browning and Alleviates Obesity-Induced Metabolic Dysfunction in an HO-1-Dependent Fashion

Abstract

Recent studies suggest that PGC1-α plays a crucial role in mitochondrial and vascular function, yet the physiological significance of PGC1α and HO expression in adipose tissues in the context of obesity-linked vascular dysfunction remains unclear. We studied three groups of six-week-old C57BL/6J male mice: (1) mice fed a normal chow diet; (2) mice fed a high-fat diet (H.F.D.) for 28 weeks, and (3) mice fed a high-fat diet (H.F.D.) for 28 weeks, treated with adipose-specific overexpression of PGC-1α (transgenic-adipocyte-PGC-1α) at week 20, and continued on H.F.D. for weeks 20–28. R.N.A. arrays examined 88 genes involved in adipocyte proliferation and maturation. Blood pressure, tissue fibrosis, fasting glucose, and oxygen consumption were measured, as well as liver steatosis, and the expression levels of metabolic and mitochondrial markers. Obese mice exhibited a marked reduction of PGC1α and developed adipocyte hypertrophy, fibrosis, hepatic steatosis, and decreased mitochondrial respiration. Mice with adipose-specific overexpression of PGC1-α exhibited improvement in HO-1, mitochondrial biogenesis and respiration, with a decrease in fasting glucose, reduced blood pressure and fibrosis, and increased oxygen consumption. PGC-1α led to the upregulated expression of processes associated with the browning of fat tissue, including UCP1, FGF21, and pAMPK signaling, with a reduction in inflammatory adipokines, NOV/CCN3 expression, and TGFβ. These changes required HO-1 expression. The R.N.A. array analysis identified subgroups of genes positively correlated with contributions to the browning of adipose tissue, all dependent on HO-1. Our observations reveal a positive impact of adipose-PGC1-α on distal organ systems, with beneficial effects on HO-1 levels, reversing obesity-linked cardiometabolic disturbances.

Jiangtang Sanhao formula ameliorates skeletal muscle insulin resistance via regulating GLUT4 translocation in diabetic mice

“…SIRT1 is one of the most extensively described sirtuins. Its deacetylation of PGC-1α has kept being the research emphasis on energy metabolism and mitochondrial biogenesis of cells ( Tang, 2016 ; Shen et al, 2022 ). Notably, SIRT1 also belongs to the downstream target of AMPK, because the deacetylation of SIRT1 is dependent on nicotinamide adenine dinucleotide (NAD + ), which is enhanced by AMPK.…”

Effect of Physical Activity/Exercise on Oxidative Stress and Inflammation in Muscle and Vascular Aging

“…In older humans, muscle atrophy and decreased physical activity, key factors in the development of sarcopenia, have been linked to decreased levels of PGC-1α [ 61 , 65 ]. Furthermore, PGC-1α expression stimulates the expression of antioxidant genes, including heme oxygenase 1 (HO-1) and is increased in tissues and organs with high-energy metabolic loads, e.g., adipose tissue, cardiac, and skeletal muscle [ 66 ].…”

Cucurbitacin B-, E-, and I-Induced Browning of White Adipocytes Is Promoted by the Inhibition of Phospholipase D2

“…In addition, PRDM16 and PGC1a have been reported to be transcriptional regulatory factors that regulate the formation of brown and beige adipocytes in mature white adipocytes. PRDM16 induces the differentiation of white adipocytes into brown adipocytes and induces the expression of its partner PGC1a, which subsequently induces an increase in UCP-1 expression [ 10 , 12 , 29 ]. RT-qPCR and Western blotting analyses were performed to measure the expression levels of PRDM16 and PGC1a, which regulate the expression of the thermogenic gene UCP-1.…”

“…Furthermore, mitochondrial biosynthesis is the process of generating new mitochondria, and PGC-1a is a key regulator of mitochondrial biosynthesis that can activate the expression of downstream mitochondrial factors, including UCP-1, in various signaling pathways. Brown adipocytes also induce the expression of native UCP-1 in the inner mitochondrial membrane [ 10 , 12 , 27 ]. To confirm the effect of Cu B, Cu E, and Cu I on mitochondrial biosynthesis, the mitochondrial mass was measured using a confocal microscope after staining with MitoTracker.…”

“…Beige adipocyte UCP-1 plays an important role in thermogenesis by consuming mitochondrial oxidative energy rather than storing it by releasing it as heat rather than using it to generate ATP. Beige adipocytes have the characteristics of UCP-1 expression and mitochondrial production and express various beige-adipocyte-specific markers such as PRDM16 and PGC1a [ 7 , 11 , 12 ]. Brown and beige adipocytes contribute to the regulation of energy consumption in the body; thus, promoting the differentiation of white adipocytes into brown and beige adipocytes can help alleviate the side effects of white fat and improve various metabolic diseases.…”