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1.
Sci Rep ; 13(1): 2651, 2023 02 14.
Article in English | MEDLINE | ID: mdl-36788340

ABSTRACT

Obesity induces a chronic inflammatory state associated with changes in adipose tissue macrophages (ATMs). Macrophage scavenger receptor 1 (MSR1) has been implicated in the regulation of adipose tissue inflammation and diabetes pathogenesis; however, reports have been mixed on the contribution of MSR1 in obesity and glucose intolerance. We observed increased MSR1 expression in VAT of obese diabetic individuals compared to non-diabetic and single nuclear RNA sequencing identified macrophage-specific expression of MSR1 in human adipose tissue. We examined male Msr1-/- (Msr1KO) and WT controls and observed protection from obesity and AT inflammation in non-littermate Msr1KO mice. We then evaluated obese littermate Msr1+/- (Msr1HET) and Msr1KO mice. Both Msr1KO mice and Msr1HET mice became obese and insulin resistant when compared to their normal chow diet counterparts, but there was no Msr1-dependent difference in body weight, glucose metabolism, or insulin resistance. Flow cytometry revealed no significant differences between genotypes in ATM subtypes or proliferation in male and female mice. We observed increased frequency of proliferating ATMs in obese female compared to male mice. Overall, we conclude that while MSR1 is a biomarker of diabetes status in human adipose tissue, in mice Msr1 is not required for obesity-associated insulin resistance or ATM accumulation.


Subject(s)
Insulin Resistance , Obesity , Scavenger Receptors, Class A , Animals , Female , Male , Mice , Adipose Tissue/metabolism , Inflammation/metabolism , Insulin/metabolism , Insulin Resistance/genetics , Mice, Inbred C57BL , Obesity/complications , Obesity/genetics , Obesity/metabolism , Scavenger Receptors, Class A/metabolism
2.
Mol Metab ; 66: 101642, 2022 12.
Article in English | MEDLINE | ID: mdl-36402403

ABSTRACT

BACKGROUND: Adipose tissue macrophages (ATMs) are a well characterized regulator of adipose tissue inflammatory tone. Previously defined by the M1 vs M2 classification, we now have a better understanding of ATM diversity that departs from the old paradigm and reports a spectrum of ATM function and phenotypes in both brown and white adipose tissue. SCOPE OF REVIEW: This review provides an updated overview of ATM activation and function, ATM diversity in humans and rodents, and novel ATM functions that contribute to metabolic homeostasis and disease. MAJOR CONCLUSIONS: While the paradigm that resident ATMs predominate in the lean state and obesity leads to the accumulation of lipid-associated and inflammatory ATMs still broadly remains rigorously supported, the details of this model continue to be refined and single cell data provide new insight into ATM subtypes and states.


Subject(s)
Adipose Tissue , Inflammation , Humans , Inflammation/metabolism , Adipose Tissue/metabolism , Macrophages/metabolism , Obesity/metabolism , Adipose Tissue, White/metabolism
3.
FASEB J ; 28(5): 2272-80, 2014 May.
Article in English | MEDLINE | ID: mdl-24448824

ABSTRACT

Enzyme or gene replacement therapy with acid α-glucosidase (GAA) has achieved only partial efficacy in Pompe disease. We evaluated the effect of adjunctive clenbuterol treatment on cation-independent mannose-6-phosphate receptor (CI-MPR)-mediated uptake and intracellular trafficking of GAA during muscle-specific GAA expression with an adeno-associated virus (AAV) vector in GAA-knockout (KO) mice. Clenbuterol, which increases expression of CI-MPR in muscle, was administered with the AAV vector. This combination therapy increased latency during rotarod and wirehang testing at 12 wk, in comparison with vector alone. The mean urinary glucose tetrasaccharide (Glc4), a urinary biomarker, was lower in GAA-KO mice following combination therapy, compared with vector alone. Similarly, glycogen content was lower in cardiac and skeletal muscle following 12 wk of combination therapy in heart, quadriceps, diaphragm, and soleus, compared with vector alone. These data suggested that clenbuterol treatment enhanced trafficking of GAA to lysosomes, given that GAA was expressed within myofibers. The integral role of CI-MPR was demonstrated by the lack of effectiveness from clenbuterol in GAA-KO mice that lacked CI-MPR in muscle, where it failed to reverse the high glycogen content of the heart and diaphragm or impaired wirehang performance. However, the glycogen content of skeletal muscle was reduced by the addition of clenbuterol in the absence of CI-MPR, as was lysosomal vacuolation, which correlated with increased AKT signaling. In summary, ß2-agonist treatment enhanced CI-MPR-mediated uptake and trafficking of GAA in mice with Pompe disease, and a similarly enhanced benefit might be expected in other lysosomal storage disorders.


Subject(s)
Adrenergic beta-2 Receptor Agonists/metabolism , Clenbuterol/pharmacology , Glycogen Storage Disease Type II/metabolism , Glycogen/metabolism , Receptor, IGF Type 2/metabolism , alpha-Glucosidases/metabolism , Animals , Cations , Densitometry , Dependovirus/metabolism , Extremities/physiology , Genetic Vectors , HEK293 Cells , Humans , Lysosomes/metabolism , Mice , Mice, Knockout , Muscle, Skeletal/metabolism , alpha-Glucosidases/genetics
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