Chloroquine attenuates diet-induced obesity and glucose intolerance through a mechanism that might involve FGF-21, but not UCP-1-mediated thermogenesis and inhibition of adipocyte autophagy

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Ortiz-Silva, Milene ; Leonardi, Bianca F. ; Castro, Erique ; Peixoto, Albert S. ; Gilio, Gustavo R. ; Oliveira, Tiago E. ; Tomazelli, Caroline A. ; Andrade, Maynara L. ; Moreno, Mayara F. ; Belchior, Thiago ; Magdalon, Juliana ; Vieira, Thayna S. ; Donado-Pestana, Carlos M. ; Festuccia, William T.

• Document type: Journal article
• Source: Molecular and Cellular Endocrinology; v. 578, p. 11-pg., 2023-09-26.

Abstract

Chloroquine diphosphate (CQ), a weak base used to inhibit autophagic flux and treat malaria and rheumatoid diseases, has been shown, through unknown mechanisms, to improve glucose and lipid homeostasis in patients and rodents. We investigate herein the molecular mechanisms underlying these CQ beneficial metabolic actions in diet-induced obese mice. For this, C57BL6/J mice fed with either a chow or a high-fat diet (HFD) and uncoupling protein 1 (UCP-1) KO and adipocyte Atg7-deficient mice fed with a HFD were treated or not with CQ (60 mg/kg of body weight/day) during 8 weeks and evaluated for body weight, adiposity, glucose homeostasis and brown and white adipose tissues (BAT and WAT) UCP-1 content. CQ reduced body weight gain and adipose tissue and liver masses in mice fed with a HFD, without altering food intake, oxygen consumption, respiratory exchange ratio, spontaneous motor activity and feces caloric content. CQ attenuated the insulin intolerance, hyperglycemia, hyperinsulinemia, hypertriglyceridemia and hypercholesterolemia induced by HFD intake, such effects that were associated with increases in serum and liver fibroblast growth factor 21 (FGF-21) and BAT and WAT UCP-1 content. Interestingly, CQ beneficial metabolic actions of reducing body weight and adiposity and improving glucose homeostasis were preserved in HFD-fed UCP-1 KO and adipocyte Atg7 deficient mice. CQ reduces body weight gain and adiposity and improves glucose homeostasis in diet-induced obese mice through mechanisms that might involve FGF-21, but not UCP1-mediated nonshivering thermogenesis or inhibition of adipocyte autophagy. (AU)

• FAPESP's process: 15/19530-5 - Involvement of the nutrient sensor mTOR in the development of obesity associated chronic metabolic diseases
• Grantee: William Tadeu Lara Festuccia
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/05406-3 - Involvement of autophagy in the metabolic and inflammatory changes induced by mTORC1 inactivation in adipocytes
• Grantee: Milene Ortiz Silva
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 16/23169-9 - Involvement of mTORC1 and 2 and PPARgamma in the regulation of leukocyte profile, recruitment and activation of brown adipose tissue and beige adipocytes induced by cold exposure
• Grantee: Érique de Castro
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 20/04159-8 - mTORC2 and mTORC1 biology and involvement in steatosis development and progression to steatohepatitis and hepatocellular carcinoma
• Grantee: William Tadeu Lara Festuccia
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/01763-4 - Characterization of the molecular mechanisms determining the energy balance, glucose homeostasis and hepatomegaly in mice with severe lipodystrophy
• Grantee: William Tadeu Lara Festuccia
• Support Opportunities: Regular Research Grants