Role of β1‐adrenoceptor in increased lipolysis in cancer cachexia

Abstract

Increased production of hormone-sensitive lipase (HSL) protein has been demonstrated to be the major cause behind enhanced lipolysis in cancer cachexia. The mechanism governing this alteration is unknown and was presently investigated. This study was conducted to detect the expression of relevant receptors in the adipocytes of cancer cachexia patients, and to elucidate their implication in the increased lipolysis. Gene expressions of b1-adrenoceptor (ADRB1), b2-adrenoceptor (ADRB2), b3-adrenoceptor (ADRB3), a2C-adrenoceptor (ADRA2C), natriuretic peptide receptor A (NPRA), insulin receptor (INSR), and HSL were determined in adipose tissues of 34 patients by real-time PCR. Protein levels of ADRB1 and HSL were determined by western blot analysis. b1-Adrenoceptor (ADRB1) was also detected by immunofluorescence staining. mRNA expressions of both ADRB1 and HSL were approximately 50% elevated selectively in the cachexia group, whereas mRNA levels of the other receptors were unchanged. b1-Adrenoceptor (ADRB1) protein expression was 1.5-fold increased in cachexia as compared with the cancer controls, and 3-fold increased as compared with nonmalignant controls, and was confirmed as a membrane protein in adipocytes by immunofluorescence. Hormone-sensitive lipase (HSL) protein expression was 2-2.5-fold increased selectively in cachectic patients. There was a positive correlation between the protein expressions of ADRB1 and HSL. As much as approximately 50% of the variations in HSL protein expression could be explained by variations in ADRB1 protein expression. There was a link between ADRB1 protein level and lipolytic rate. Increased ADRB1 expression may account for some of the functional changes of HSL in patients with cancer cachexia. (Cancer Sci 2010; 101: 1639-1645 B ody fat depletion is a hallmark of cancer cachexia, a complex clinical syndrome associated with increased morbidity and mortality.(1-4) As the largest reservoir of energy stores and a major endocrine organ, white adipose tissue (WAT) plays a crucial metabolic role in regulating energy flux, plasma lipid levels, and glucose uptake. In cachectic patients, excessive fat consumption results in energy shortage and metabolic disturbances such as elevated serum levels of free fatty acids (FFAs) and glucose resistance, which interferes therapy against tumors. (5,6) Therefore, it is of value to understand the mechanisms behind fat loss in cancer cachexia. Antilipolysis treatment is especially meaningful for attenuating the progressive wasting, since fat deprivation often precedes and progresses faster than muscle atrophy in cancer cachexia. (7,8) However, fat tissue wasting is not well established in cancer cachexia, as indicated by recent consensus.(9) At present, very little is known about the factors promoting loss of adipose tissue in cancer patients. (10)(11)(12) Although decreased lipogenesis may contribute, increased lipolysis has been revealed the primary cause. (13)(14)(15)(16) In recent years, adipose lipolysis has been found to be under tight regulation b...

Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer

“…While β2-AR undoubtedly plays an important role in breast cancer, our data show that β1-AR and β3-AR are expressed more in breast cancer tissue relative to normal mammary epithelium at the protein level. Indeed, β1-AR and β3-AR are reportedly involved in cancer processes, whereby β1-AR has been shown to contribute to enhanced lipolysis in cancer cachexia [44] and β3-AR missense mutations have been correlated with obesity related breast cancer in African-Americans [45]. ADRB mRNA expression was not significantly different between normal and cancer cell lines, suggesting some form of translational or post-translational regulation likely contributes to the differential expression of β1-AR and β3-AR protein levels between the normal and malignant tissues.…”

Social overcrowding as a chronic stress model that increases adiposity in mice

“…Moreover, transgenic mice overexpressing Adrb1 in adipose tissue exhibit increased lipolytic rate and are partially resistant to diet-induced obesity (Soloveva et al, 1997). On the other hand, increased expression of Adrb1 mRNA and protein were detected in the WAT of patients with cancer cachexia, a condition exhibiting enhanced lipolysis (Cao et al, 2010a). …”

Hydroxysafflor yellow A (HYSA) inhibited the proliferation and differentiation of 3T3-L1 preadipocytes

“…Studies performed by Large et al (1999) showed that the lipolysis capacity and HSL mRNA and protein levels in subcutaneous adipose tissue were all significantly reduced in obese patients in comparison with non-obese subjects. Furthermore, expressions of HSL mRNA and protein in cachexia patients increased by 50 % and 1-2.5-fold, respectively, compared with both weight-stable cancer controls and nonmalignant controls (Agustsson et al 2007;Cao et al 2010). All of these findings indicated that HYSA could suppress the content of triglycerides in adipocytes by promoting the lipolysis, and will have beneficial action in the anti-obesity field.…”