Mitochondrial Energy Metabolism in the Regulation of Thermogenic Brown Fats and Human Metabolic Diseases

Abstract

Brown fats specialize in thermogenesis by increasing the utilization of circulating blood glucose and fatty acids. Emerging evidence suggests that brown adipose tissue (BAT) prevents the incidence of obesity-associated metabolic diseases and several types of cancers in humans. Mitochondrial energy metabolism in brown/beige adipocytes regulates both uncoupling protein 1 (UCP1)-dependent and -independent thermogenesis for cold adaptation and the utilization of excess nutrients and energy. Many studies on the quantification of human BAT indicate that mass and activity are inversely correlated with the body mass index (BMI) and visceral adiposity. Repression is caused by obesity-associated positive and negative factors that control adipocyte browning, de novo adipogenesis, mitochondrial energy metabolism, UCP1 expression and activity, and noradrenergic response. Systemic and local factors whose levels vary between lean and obese conditions include growth factors, inflammatory cytokines, neurotransmitters, and metal ions such as selenium and iron. Modulation of obesity-associated repression in human brown fats is a promising strategy to counteract obesity and related metabolic diseases through the activation of thermogenic capacity. In this review, we highlight recent advances in mitochondrial metabolism, thermogenic regulation of brown fats, and human metabolic diseases.

Angiotensin II participates in mitochondrial thermogenic functions via the activation of glycolysis in chemically induced human brown adipocytes

“…This is further supported by the observation that continuous treatment with Ang II decreased the phosphorylation of HSL and CREB as downstream events in the cAMP signalling pathway (Supplementary Fig. S7 B) 41 . However, transient treatment with Ang II enhanced the phosphorylation of CREB, but not of HSL.…”

“…Our study also found that the Ang II-activated mitochondrial energy status led to the repression of UCP1 transcription, similar to the feedback regulation described above. These results may partially explain the obesity-associated repression of UCP1 expression under the hyperactivation of the RAS during obesity 19 , 41 .

Figure 7 A schematic illustration of Ang II effects on metabolic reprogramming and mitochondrial energy metabolism in ciBAs.

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“…Under cold conditions, blood Ang II and NE levels increase via the activation of the SNS 30 – 32 . UCP1 expression and lipid lipolysis are activated for thermogenesis through the cAMP signalling pathway initiated by the activation of βAR by NE 41 . To evaluate the effects of Ang II on βAR-mediated thermogenesis, Ang II and either isoproterenol (Iso) or NE were simultaneously administered to ciBAs (Fig.…”

“…The effects of Ang II on glucose and lipid metabolism were exerted through the Ang II/AGTR1 axis, and treatment with telmisartan largely abolished these effects. We previously proposed a feedback regulation between mitochondrial energy status and thermogenic UCP1 transcription in ciBAs 40 , 41 . MMP induced by enriched free fatty acids, mimicking obese conditions, downregulated UCP1 transcription likely to avoid excess heat generation.…”

The Crosstalk between Gut Microbiota and White Adipose Tissue Mitochondria in Obesity

“…The mitochondrial metabolism (mitochondrial energy metabolism, and UCP1 expression/activity) in BAT tissues is also impaired by obesity, as reported in clinical and preclinical studies [ 73 , 74 ].…”