Metformin improves neurobehavioral impairments of streptozotocin-treated and western diet-fed mice: Beyond glucose-lowering effects.

Brain insulin resistance has been pointed to as a possible link between diabetes and neuropsychiatric disorders; therefore, therapeutic approaches using anti-diabetic drugs to improve insulin levels or signaling could prevent type 1 (T1D) and type 2 diabetes mellitus (T2D)-induced brain dysfunction. The present study aimed to determine whether metformin exerts beneficial effects on metabolic and neurobehavioral outcomes in the streptozotocin (STZ)-induced T1D model and western diet (WD)-induced obesity model in male Swiss mice. T1D was induced by intraperitoneal injection of STZ (50 mg/kg, for five consecutive days). The animals were then treated daily with saline or metformin (200 mg/kg/day, oral gavage), and a battery of tests recapitulating different neurobehavioral anomalies related to anxiogenic/depressive-like phenotype was conducted after 18 days. WD-induced obesity was modeled in mice by high-fat and high-fructose diet (HFFD) feeding for 15 days. In the sequence, control and diet-induced obesity mice were treated daily with saline or metformin (200 mg/kg/day), and a battery of behavioral tests was performed after 17 days. STZ injection and WD feeding induced metabolic and neurobehavioral impairments in mice. Remarkably, metformin improved the metabolic and neurobehavioral parameters in WD-induced obesity mice. Moreover, metformin ameliorated STZ-induced neurobehavioral deficits while it failed to improve the associated metabolic impairments. The beneficial effects of metformin in STZ-induced neurobehavioral impairments were not mediated by improving peripheral insulin signaling. Our results suggest that conventional diabetes treatment could be repurposed to simultaneously improve neurobehavioral symptoms and diabetes.

A selanylimidazopyridine (3-SePh-IP) reverses the prodepressant- and anxiogenic-like effects of a high-fat/high-fructose diet in mice.

OBJECTIVE: While chronic feeding with high-fat or high-sugar diets is known related to obesity and type 2 diabetes, later data have indicated that it is also related to depression and anxiety appearance. In this regard, multi-target drugs raise considerable interest as promising therapeutic solutions to complex diseases. Considering the pharmacological effects of the imidazopyridine-derivative moiety imidazo[1,2-a]pyridine and the organoselenium molecules, the combination of both could be a feasible strategy to develop efficient drugs to handle obesity and related comorbidities, for example dyslipidemia and mood disorders. METHODS: The antidepressant- and anxiolytic-like properties of a selanylimidazopyridine compound, 2-Phenyl-3-(phenylselanyl)imidazo[1,2-a]pyridine (3-SePh-IP), were evaluated on high-fat/high-fructose diet (HFFD)-fed female Swiss mice. KEY FINDINGS: Our results showed that a short-term HFFD (16 days) could promote a significant body weight gain, hypercholesterolemia, glucose intolerance, and anxiety- and depressive-like behaviour in mice. Concomitant treatment with 3-SePh-IP (10 mg/kg; i.p.) attenuated the HFFD-induced increase in cholesterol levels and blunted the anxiety- and depressive-like behaviour in mice. CONCLUSIONS: 3-SePh-IP holds multimodal pharmacological properties, which provide a rationale for further studies, for example to assess the underlying mechanisms linked to its anxiolytic- and antidepressive-like activities.

Impact of different fructose concentrations on metabolic and behavioral parameters of male and female mice.

Clinical evidence has shown that a high consumption of sugar-sweetened beverages is a risk factor for developing obesity and metabolic syndrome. There has also been increasing interest in the potential effects of high-fructose intake on behavior. The present study evaluated sex differences in behavioral and metabolic characteristics in response to chronic fructose intake in mice. Swiss mice (3-months-old) had access to tap water or fructose-water solution (at 15% or 30% w/v) ad libitum for nine weeks. After the 8 weeks, the mice were submitted to a battery of behavioral tests. A glucose tolerance test was performed one day after these behavioral tests, and the next day blood was collected for biochemical analysis. At a 15% concentration, fructose-intaking resulted in higher plasma cholesterol levels and glucose intolerance in mice that paralleled with a passive stress-coping behavior in the female mice and lower self-care behavior in the male and the female mice. At a 30% concentration, fructose-intaking resulted in higher body mass gain and higher plasma cholesterol and triglycerides levels in the male and the female mice, whereas glucose intolerance was more pronounced in the male mice. Spatial memory impairments and lower self-care behavior were observed in the male and the female mice, while passive stress-coping behavior was observed only in the female mice. Collectively, high-fructose intake induces metabolic and behavioral alterations in mice, with the males being more susceptible to glucose metabolism dysfunctions and the females to depressive-like endophenotypes.

Switching from high-fat feeding (HFD) to regular diet improves metabolic and behavioral impairments in middle-aged female mice.

Obesity represents a risk factor for metabolic syndrome and cardiovascular and psychiatric disorders. Excessive caloric intake, particularly in dietary fats, is an environmental factor that contributes to obesity development. Thus, the observation that switching from long-standing dietary obesity to standard diet (SD) can ameliorate the high-fat diet-induced metabolic, memory, and emotionality-related impairments are particularly important. Herein we investigated whether switching from the high-fat diet (HFD) to SD could improve the metabolic and behavioral impairments observed in middle-aged females C57Bl/6 mice. During twelve weeks, the animals received a high-fat diet (61 % fat) or SD diet. After 12-weeks, the HFD group's diet was switched to SD for an additional four weeks. It was observed a progressive deleterious effect of HFD in metabolic and behavioral parameters in mice. After four weeks of HFD-feeding, the animals showed glucose intolerance and increased locomotor activity. A subsequent increase in the body mass gain, hyperglycemia, and depressive-like behavior was observed after eight weeks, and memory impairments after twelve weeks. After replacing the HFD to SD, it was observed an improvement of metabolic (loss of body mass, normal plasma glucose levels, and glucose tolerance) and behavioral (absence of memory and emotional alterations) parameters. These results demonstrate the temporal development of metabolic and behavioral impairments following HFD in middle-age female mice and provide new evidence that these alterations can be improved by switching back the diet to SD.